(1997) 11, 1999–2021  1997 Stockton Press All rights reserved 0887-6924/97 $12.00

REVIEW

Molecular of childhood hematological malignancies JA Martinez-Climent

Department of Hematology and Oncology, Hospital Clinico, University of Valencia, Spain

Cytogenetic and molecular analyses are essential for the specific ALL subgroups showing distinct immunologic and classification of childhood hematologic malignancies. Nearly clinical features, such as the pre-B ALL with t(1;19), have been all children with leukemia should have an adequate cytogenetic 1,6,7 analysis which in 80–90% is expected to show clonal chromo- defined. Moreover, there are subtypes of ALL and AML somal abnormalities. Moreover, with the availability of appro- that are identifiable primarily by chromosome analysis, for priate gene probes and sophisticated molecular techniques, example ALL with the or AML with genetic rearrangements become detectable in the majority of erythrophagocytosis and t(8;16).3,8 Apart from the diagnostic leukemia patients. Genetic abnormalities often associate with assessment, cytogenetic findings sometimes correlate with particular clinical–biological characteristics of the disease. In clinical outcome and thus, also serve as prognostic parameters ALL, for example, genetic alterations together with distinct 1,4 immunologic and clinical features, define various subgroups. which may affect the therapeutic decision. In AML, unique cytogenetic rearrangements have been ident- Several leukemia phenotype-specific chromosomal translo- ified and associated with distinct morphological subgroups. cation or inversion breakpoints have been cloned. They were Apart from the diagnostic assessment, cytogenetic studies pro- subsequently shown to interrupt oncogenes which are thought vide valuable prognostic information which may influence to play a causative role in leukemogenesis.9 Chromosomal treatment choices. Molecular analysis has also become of deletions, which result in the loss of the so-called tumor important value in the management of children with , suppressor genes, are much less common in pediatric as it serves, for example, to identify genetic abnormalities not 4,10 detected by chromosomal analysis and to monitor residual dis- leukemias. Molecular identification of genes participating ease during treatment and follow-up. Thus, genetic analyses of in genetic alterations has provided clinicians with breakpoint- leukemic cells provide information of clinical relevance as well specific gene probes or sequence information to be used in as contributing to our understanding of leukemogenesis. Alter- new DNA or RNA diagnostic technology as a tool of critical native classifications of acute leukemias which take into importance in the management of children with leukem- account genetic information are being proposed. The available 11,12 cytogenetic and molecular data have then to be included in ias. This includes identification of molecular abnormali- clinical protocols, either by selecting individualized therapies ties not detected by chromosomal analysis as well as monitor- in certain leukemia subtypes or by modifiying treatment ing residual disease during treatment and follow-up.13,14 according to quantification of residual disease. We are closer Finally, the abnormal fusion transcripts and chimeric proteins to our main goal which is not only to classify 100% of childhood derived from karyotypic abnormalities are also now targeted leukemias accurately, but to cure all of them. by novel therapeutic approaches.15 Keywords: cytogenetics; molecular analysis; leukemia; lympho- blastic; myeloid; children Here I review the cytogenetic and molecular abnormalities associated with childhood leukemias. Firstly, a clinically use- ful genetic classification of childhood ALL is updated, by revisiting the classical cytogenetic abnormalities and examin- Introduction ing in detail the newly described rearrangements of TEL- AML1, p16INK4a/p15INK4b, and TAL1 genes. Secondly, empha- Leukemia is the most common type of childhood cancer. sis is given to the classification and prognostic significance of Acute lymphoblastic leukemia (ALL) represents approximately the genetic abnormalities in AML and MDS, with particular 80% of all pediatric leukemias, whereas acute myeloid leuke- focus on those aspects which differ in children and adults. mia (AML) comprises 15–20% of cases. Other types of Methods and nomenclature of the molecular and cytogenetic myeloid neoplasms, such as the myelodysplastic syndromes analyses are described in Refs 12 and 16, respectively. (MDS) or chronic myeloid leukemia (CML), are seldom seen, and only a few pediatric cases of chronic lymphocytic leuke- mia, the most frequent leukemia in adulthood, have been described.1 Incidence of karyotypic abnormalities in childhood Cytogenetic analysis has become a powerful tool with leukemias which to classify acute leukemias.2,3 Recurrent chromosomal abnormalities present in malignant cells often correlate closely Currently, when the bone marrow sample is sent to the labora- with specific clinical and biological characteristics of the dis- tory and processed properly, nearly all children with leukemia ease.2,4 In AML, unique cytogenetic rearrangements associate should have an adequate cytogenetic analysis, and in 80–90% with distinct morphological subgroups, such as the t(15;17) in of leukemias a clonal chromosomal abnormality should be acute promyelocytic leukemia.1,4,5 In ALL, cytogenetic- identified.2,4,6,16–21 Moreover, genetic rearrangements should be detectable in most leukemia patients with the help of flu- orescence in situ hybridization (FISH) and other molecular Correspondence: JA Martinez-Climent, Laboratory of Hematology and techniques providing the availability of appropriate DNA Molecular Cytogenetics, Department of Hematology and Oncology, 3 Hospital Clinico, University of Valencia, Avda. Blasco Ibanez, 17, probes. Hypothetically, if all the in any given 46010 Valencia, Spain; Fax: 34 6 3862625 leukemia are identified, we may assess the genotype and thus Received 22 April 1997; accepted 23 June 1997 predict the resultant phenotype.22 Review JA Martinez-Climent 2000

Figure 1 Bone marrow karyotypes of metaphase cells from children with acute leukemia. G banding of the chromosomes has been performed using a trypsin-Giemsa staining technique. The abnormal chromosomes are indicated by arrows. (a) Hyperdiploidy with more than 50 chromo- somes in a 4-year-old girl with acute lymphoblastic leukemia of B cell precursor CD10+ phenotype. The complete karyotype of this cell is 53,XX,+X,+6,+8,+14,+17,+18,+21. (b) The reciprocal translocation t(1;22) in an infant with acute megakaryoblastic leukemia. The complete karyotype of this cell is 45,XX,t(1;22)(p13;q13),−2.

Acute lymphoblastic leukemia rearrangements in most cases.6,13,16,17 Extensive clinical stud- ies in the 1980s revealed the independent impact of chromo- Children with ALL who according to certain biological and somal analysis on the prognosis of such patients.24,25 The sur- clinical features are included in standard-risk therapeutic sub- vival of many high-risk cytogenetic subgroups of ALL has groups presently enjoy a cure rate of more than 80%.1,23 For improved remarkably with currently available therapies.26–28 many years, cytogenetic analysis of ALL samples was largely This advancement, however, does not extend to children with handicapped by the poor morphology of their chromo- t(4;11) and t(9;22), who still experience a poor survival somes.24 Current cytogenetic techniques allow karyotypes of rate.6,29 excellent quality, similar to those recovered from myeloid leu- The FAB classification divides ALL into three subtypes kemia samples, to be obtained.6,16 Up to 90% of children with designated L1, L2 and L3. The correlation between these sub- untreated ALL display karyotypic abnormalities, and comp- groups and chromosomal abnormalities is poor, except for the lementary molecular techniques permit the detection of L3 which associates with t(8;14).6,8 A more detailed classi- Review JA Martinez-Climent 2001 fication of childhood ALL is achieved by taking into account mosomes (72 vs 86%). The authors explained the poorer out- specific genotypes and immunophenotypes (Table 1). come of the first subgroup by the presence of i(17q) chromo- Although there are cases which overlap two subgroups (ie some which has been linked to worse prognosis.30 Of these hyperdiploid cases with Philadelphia chromosome), the fol- 182 cases, only three had a T cell ALL. Major cytogenetic lowing classification is applicable to more than 90% of child- abnormalities were seen in nine cases (four t(1;19), three hood ALL. Each leukemia subgroup exhibits distinctive clini- t(9;22), two t(11q23)).30 In another study involving children cal and prognostic features which often determine individual with ALL and hyperdiploidy, the presence of additional struc- therapeutic approaches.3,8,16,17,22,26,29 tural abnormalities were more frequent in the group with 47– 50 chromosomes than in the group of ALL with more than 50 chromosomes. Eleven of these 86 children with 47–50 chro- Hyperdiploidy and common ALL mosomes disclosed major recurrent abnormalities (six t(1;19), three t(9;22), two t(11q23)), and T cell ALLs (seven of 86, 8%) Children suffering from ALL are being grouped according to were also more common than in the group with more than the modal number of chromosomes present in malignant cells. 50 chromosomes.31 Clinically, children with 47–50 ALL had Hyperdiploid karyotypes with 50 or more chromosomes are unfavorable prognostic features: older age, higher WBC and found in 25–30% of childhood ALL. Another 8–15% of child- higher serum LDH.30,31 Survival of this subgroup was reported hood ALLs disclose hyperdiploidy with 47–49 chromosomes in previous studies as being intermediate,16,23–25,28,29 probably (Figure 1a).16,30,31 Almost half of ALL cases with 50 or more influenced negatively by cases with T cell phenotype or with chromosomes also display structural cytogenetic abnormali- unfavorable translocations such as t(9;22), t(4;11) or t(1;19). ties, frequently duplications of 1q and isochromosome of However, intensified therapy has improved the clinical out- 17q.30 These patients tend to present several factors associated come for children with ALL and 47–50 chromosomes: EFS at with favorable prognosis in ALL: age between 2 and 10 years, 4 years was 77%, similar to the subgroup with Ͼ50 chromo- leukocyte count less than 10 000 × 106/l, L1 morphology, and somes.30,31 Therefore, hyperdiploid ALL cases with a precursor an early pre-B immunophenotype (CD10+).16 Owing to the B cell phenotype CD10+ can be considered as a distinct clini- lack of recurrent translocations in the majority of these cal–biological subgroup, except for a few cases with other patients, no genes which specifically associate with this group recurrent abnormalities or T cell phenotype, which should be have beeen cloned. As a consequence, PCR cannot be applied excluded from this subgroup. Whether cases with 47–50 and to monitor the disease, but interphase FISH has been useful Ͼ50 chromosomes are different types of ALL needs to be re- in detecting minimal residual disease (MRD) and early evaluated following the exclusion of the above mentioned relapses.32,33 Hyperdiploid cases are also identified by flow cases from the entire group. cytometric analysis which detects elevated blast cell DNA content, a factor associated with favorable prognosis.34,35 Children with ALL with Ͼ50 chromosomes experience a cure ALL with hypodiploidy rate of more than 80% with antimetabolite chemo- therapy.1,23,26–31 This favorable outcome may be explained by Hypodiploidy (Ͻ46 chromosomes) is found in 7–8% of cases the high sensibility of cells to antimetabolite drugs.36 In a of childhood ALL, and despite lacking most ALL high-risk review of 182 children with ALL and hyperdiploidy Ͼ50, the prognostic factors, these patients do far worse than those with 5-year probability of event-free survival (EFS) for patients with hyperdiploidy.6,16,24,25,29,37 Rare cases of ALL with modal 51–55 chromosomes was less than for those with 56–67 chro- number of chromosomes near haploidy (Ͻ30 chromosomes)

Table 1 Classification of childhood ALL according to genetic analyses

Genetic subgroup Rearranged Phenotype Incidence Associated features genes %

Hiperdiploidy ? common 25–35 age 2–10 years, no aggressive features, excellent CD10+ prognosis Hipodiploidy ? pre-B 5–8 no aggressive features, poor prognosis t(4;11),t(11q23)a MLL-othersa early-pre-B 5–8 infants, hyperleukocytosis, CNS disease, massive CD10− organomegaly, not curable with chemotherapy t(1;19) PBX1-E2A pre-B 5–8 no aggressive features, intermediate prognosis t(12;21) TEL-AML1 early-pre-B 16–22 age 1–10 years, no aggressive features, favorable pre-B prognosis t(9;22) ABL-BCR early-pre-B 5 variable aggressive features, very poor prognosis pre-B t(8;14) -IGH/K/L mature-B-cell 1–3 abdominal tumors, CNS disease, tumor lysis FAB-L3 syndrome, curable disease, favorable prognosis 14q11,7q35,7p15b TCR genes T cell 15 males, mediastinal mass, intermediate–good TAL1 prognosis t(5;14) IL3-IGH B-Eoc Ͻ1 very rare aAF4 at 4q21, ENL at 19p13.3 in the t(11;19), AF6 at 6q27 in the t(6;11) are the most frequent. bMultiple translocations and inversions involving TCR gene breakpoints. cALL of precursor B cell phenotype with peripheral eosinophilia. Review JA Martinez-Climent 2002 have been reported; this finding is associated with a short median survival and poor prognosis, and it is therefore important to distinguish these cases from the hyperdiploid group.6,24,29,37

Early-pre-B (CD10-) ALL with rearrangement of 11q23/MLL gene

Cytogenetic abnormalities of band 11q23 were identified in 53 of 669 (8%) successfully karyotyped cases of pediatric ALL.38 The most common abnormality, t(4;11)(q21;q23), is present in 2–5% of ALLs, especially in infants less than 1 year old with hyperleukocytosis and extramedullary disease. As in other children with translocations of band 11q23 (t(11q23)), leukemic cells display L1 or L2 morphology, early pre-B immunophenotype (CD10 negative), and frequent co- expression of myeloid markers.6,38–41 The MLL gene located in 11q2342 is found rearranged in t(4;11) and in most of the other common and uncommon t(11q23).43 Moreover, 70% of infants aged less than 1 year with ALL show a MLL gene rearrangement.13,44,45 The AF-4 gene at 4q21 is fused to MLL in t(4;11); MLL/AF4 fusion transcripts are detectable by reverse-transcriptase PCR (RT-PCR). This technique is especially useful in tracking MRD.46,47 Another recurrent

Figure 2 FISH analysis of childhood leukemias. Examples of in situ hybridization of cosmid and YAC probes to metaphase cells of child- hood leukemias with abnormalities of band 11q23. (a) Child with ALL and a t(11;19)(q23;p13.3) identified by FISH: mapping of an MLL probe (yB22B2 YAC) to the normal at band 11q23 (top); the YAC is split and maps to the der(11) (bottom, left) and the der(19) (bottom, right). (b) Child with AML-M5 and a t(11;19) (q23;p13.1) detected by dual-color FISH. (a) Mapping of two cosmid probes which flank the MLL gene: cosmid 1.16 (red signal) and the Figure 3 Cytogenetic analysis of childhood leukemias with abnor- PGBD cosmid (green signal) to the normal chromosome 11 (bottom, malities of band 11q23. Partial karyotypes of children with t(11;19) right). The proximal probe to MLL gene (1.16, red) remains in the shown in Figure 2. The abnormal chromosomes are on the right of der(11) (top) whereas the distal probe to MLL gene (PBGD, green) is each pair. (a) Child with ALL and a t(11;19) (q23;p13.3): Giemsa stain- translocated to the der(19) (bottom, left). ing (top) and quinacrine staining (bottom) of the same cell. (b) Child with AML-M5 and a t(11;19)(q23;p13.1) in two different cells studied with G-banding. Both types of t(11;19) are difficult to detect with con- ventional cytogenetic analysis and therefore FISH and molecular stud- ies are of critical importance to identify these abnormalities. Review JA Martinez-Climent 2003 abnormality seen in less than 1% of pediatric ALL is displayed TEL rearrangement.70 Interestingly, the TEL-AML1 t(11;19)(q23;p13.3), which fuses MLL to a gene called ENL. fusion was found rarely in adult ALL (three of 107 cases)74 This translocation is difficult to detect with banding tech- and in infant ALL (none of 62 cases).75 Therefore, all newly niques, and therefore its frequency might be underestimated diagnosed childhood ALL should be screened for TEL unless complementary FISH or molecular analysis are rearrangements in order to identify patients suitable for less employed (Figures 2 and 3).44,48 Survival of children with intensive or shorter therapy. The TEL/AML1 transcript was pro- 11q23/MLL rearrangements is very short, regardless of posed as a candidate for monitoring MRD study in childhood presenting age.13,26,29,38,39,45,47,49,50 In a series of 45 children ALL of B lineage.71 The 12;21 translocation involving the TEL with ALL and 11q23 karyotypic abnormalities, 22 leukemias gene can be accompanied by a of the other TEL gene with t(11q23) and MLL rearrangements were analyzed separ- allele,76 suggesting that this deletion subsequent to t(12;21) ately from 23 cases with deletion or inversion of 11q23, provides a further proliferative advantage to the leukemic cell which lacked abnormality of the MLL gene.49 The MLL gene clone.77 Moreover, identification of two distinct commonly rearrangement resulted as a powerful determinant of survival deleted segments on 12p suggests that the putative loss of at and correlated with a much inferior outcome.38,49,50 Allogenic least two tumor suppressor genes might participate in the bone marrow transplantation (BMT) is the therapy of choice pathogenesis of these leukemias.78 Another recurring abnor- for ALL-MLL, as only exceptional cases can be cured with mality of 12p, the dic(9;12)(p12;p12), has been associated chemotherapy alone.13,29,38,39,41,49,50 with favorable prognosis in progenitor B-ALL.79

Pre-B ALL with t(1;19) Philadelphia-positive ALL

A t(1;19)(q23;p13) is present in 25% of children with pre-B The t(9;22)(q34;q11), which forms the Philadelphia chromo- ALL or in 5% of all pediatric ALL cases.51,52 The fusion tran- some (Ph) and results in transcription of the BCR-ABL fusion scripts of either the t(1;19), PBX-E2A, or the molecular product mRNA, is seen in patients with ALL as well as in those with of its variant abnormality t(17;19)(q21;p13), HLF-E2A, are CML. A t(9;22) is identified in 25–30% of adult and in 3–5% detectable by RT-PCR.52,53 Two distinct cytogenetic variations of childhood cases of ALL.1,29,80,81 At the cytogenetic level, of the t(1;19), a reciprocal balanced t(1;19) observed in 25% t(9;22) in ALL-Ph and CML are identical. However, the break- of cases, and an unbalanced der(19)t(1;19) form in 75% of point within the BCR gene on occurs in a cases, might comprise two major clinical and biological sub- more centromeric region in ALL-Ph than in CML cases. The types. The first group tends to show a hyperdiploid karyotype BCR-ABL gene in most cases of ALL-Ph is therefore shorter, and favorable prognosis, whereas the second group presents giving rise to a hybrid protein (185 kDa) smaller in size than with pseudodiploidy and an intermediate prognosis.54 How- the 210 kDa protein of CML.82–84 In two series of adult ALL, ever, the differences in outcome between the two forms seem BCR-ABL rearrangements were detected in 23–45% of inconsistent with the fact that the PBX-E2A fusion protein is patients using PCR but only in 14–22% of patients using cyto- the same in both.52 Moreover, the poor outcome reported in .85,86 Clinically it is important to distinguish patients early series associated with all t(1;19) as compared to other with ALL-Ph from those with CML in lymphoid blast phase, pre-B ALL55,56 is nowadays nullified with intensive therapy,57 which is feasible using PCR and FISH.87–89 Cytogenetics is also which may therefore also nullify the different outcomes of the useful, as the Ph will remain during the total course of the balanced and unbalanced forms. Monitoring of MRD with RT- disease in CML whereas in ALL it will disappear in complete PCR in t(1;19) ALL has been reported to be clinically remission.6,16,90–92 Children with ALL-Ph frequently show a useful.52,58 complete or partial deletion of , otherwise a rare finding in lymphoid neoplasms and CML.93 ALL-Ph shows predominantly an early B cell phenotype CD10+ with frequent Precursor B cell ALL with 12p abnormalities and co-expression of myeloid markers; however, pre-B and T cell TEL/AML1 rearrangement phenotypes are seen in 5–10% of cases.6,16,80,81,94,95 Clini- cally, patients are generally older than 10 years, have an Karyotypic translocations or deletions of the short arm of chro- increased leukocyte count and frequently suffer from CNS dis- mosome 12 are detected in more than 10% of pediatric ALL ease.80 However, in a recent study, no significant clinical dif- cases.59 However, specific recurring abnormalities such as ferences were found between childhood ALL cases with and t(6;12), t(12;18) or t(12;21) are rarely seen.6 Using FISH, the without Ph.81 Outcome is dismal for both children and adults t(12;21)(p13;q22) was identified in three of eight children with with ALL-Ph. In a series of 648 children with ALL, 21 (3.2%) ALL without a 12p abnormality by cytogenetics.60 Recently, a showed BCR/ABL rearrangement which was associated with novel gene called TEL was cloned and located on 12p13 in a shorter EFS.81 The clinical impact of monitoring residual dis- a t(5;12) translocation. TEL gene fuses to the AML1 gene in ease by quantitative PCR deserves further investigation.96 As t(12;21)(p13;q22).61–63 The TEL-AML1 fusion product was only few patients are cured with intensive chemotherapy,97 detected in 205 of 731 (28%) children with ALL of B lineage allogeneic BMT is generally considered for this sub- in several series64–73 (Table 2). Therefore, the TEL-AML1 group,6,24,25,29,80,81,94,95,98 but autologous BMT with purging fusion gene represents one of the most common genetic could also have potential value.98,99 lesions in ALL, identifying a subtype of B lineage without a hyperdiploid karyotype, including children aged between 1 and 10. It is remarkable that a proportion of cases B cell ALL (sIg+) with t(8;14) co-expressed myeloid antigens.71,73 Prognosis for these leukemias is regarded as favorable in the majority of clinical A karyotypic and molecular translocation t(8;14)(q24;q32), studies.64–66,68–72 In a uniformly treated group of 170 children otherwise characteristic of Burkitt , is also detected with ALL, outcome was superior for the 35 cases that in 85–90% of B cell ALL of L3 morphology, which is con- Review JA Martinez-Climent 2004 Table 2 TEL-AML1 fusion gene in childhood acute lymphoblastic leukemia

Author/Ref. Cases TEL/AML1+/total of cases in Associated features Outcome TEL/AML1+ vs − ALL B-ALL (%) T-ALL TEL/AML1

Romana63,64 NR 8/36 (22) NR t(12;21) detected by FISH NR No other cytogenetic abnormalities Shurtleff65 35/160 35/126 (28) 0/34 Age 1–10 years, 0% infants EFS 5 years: 92 ± 8 vs Rubnitz70 No hyperdiploidy, 70 ± 10 (P = 0.14)a No t(1;19), t(9;22), t(4;11) Borkhardt73 NR 100/352 (28) NR Age 1–10 years Relapse 3/100 vs DNA index Ͻ1.16 29/252 pre-B CD10+, CD13/33+ (9 of 37) McLean66 22/81 22/68 (32) 0/13 Age 2–9 years Relapse 0/22 vs 16/54 pre-B CD10+, CD13/33 negative (P = 0.004) Chambost72 21/88 21/78 (27) 0/10 Lower WBC No better outcome for No t(1;19), t(9;22), t(4;11) ALL with TEL/AML1+ Liang67 7/41 7/36 (19) 0/5 Age 1–10 years, no clinical differences Relapsed 0/7 vs 2/29 Cayuela71 12/45 12/35 (34) 0/10 Age 2–10 years, no clinical differences Better prognosis Schaison68 pre-B CD10+, CD13/13+ (4 of 12) BCR-ABL, MLL-AF4, EA2-PBX neg.

Total 97/415 (23%) 205/731 (28) 0/72

NR, not reported. aIn Ref. 70 using a Cox regression model adjusted for age, DNA index, race, WBC, T cell phenotype, treatment group, and CNS status, TEL rearrangement retained independent prognostic significance when comparing cases TEL+ vs TEL− (P = 0.04).

sidered a disseminated phase of .100–104 The known to harbour the T cell receptors genes: TCR-␣ and TCR- t(8;14) ALL cases constitute 1–3% of all pediatric ALL, ␦ genes within band 14q11, TCR-␥ within band 7p15, and presenting in older children with abdominal tumors and CNS TCR-␤ gene within band 7q35.11,117,121–124 These TCR genes disease.16,105,106 About 10–15% of cases harbor a variant of fuse with diverse reciprocal partner genes. One example is t(8;14), namely t(2;8)(p12;q24) or t(8;22)(q24;q11), all of t(1;14)(p34;q11), observed in 3% of childhood T cell ALL, which affect the site of the MYC proto-oncogene at band where the TCR-␣/␦ genes are juxtaposed with the TAL1 8q24.107–109 The MYC gene fuses with the immunoglobulin gene.125,126 Molecular analysis has expanded the number of heavy chain gene (IGH) at band 14q32 in the t(8;14). In t(2;8) T cell ALL with TAL1 rearrangements to 12–26% of cases.127 and t(8;22), other immnunoglobulin genes, namely the kappa Moreover, in one series, TAL1 was expressed by the malignant light chain (IGK) and lambda light chain (IGL) genes, are fused cells in more than 60% of pediatric T cell ALL which either to the MYC gene, respectively.11,109–111 Molecular monitoring disclosed TAL1 gene rearrangements (10 of 10) or had no is useful for patients suffering from the leukemic or lymphoma detectable molecular abnormalities (13 of 27).128 Therefore, form of this disease.108,112 Survival of children with B cell ALL TAL1 gene is a candidate for monitoring the disease using PCR and t(8;14) was poor when treated as other types of ALL, but in most T cell ALL.14,127,129 Similarly, HOX11 gene expression nowadays up to 80% of these patients are cured with the same has been found in up to 33% of childhood T cell ALL, despite short-term intensive chemotherapy protocols applied for Burk- the rarity of detectable cytogenetic abnormalities involving itt , including high-dose cyclophosphamide, cyta- 10q24.117,120,130,131 rabine, methotrexate and intrathecal chemotherapy.113–116 The EGIL group has proposed an immunologic classification of ALL. Here, the major subgroups of T-ALL are distinguished based on the membrane expression of TCR-␣/␤ chains (group T cell ALL with rearrangements of TCR-␣/␤ and TCR- a) and TCR-␥/␦ chains (group b).132 While several authors ␥/␦ genes agreed to separate these two clinically and phenotypically dis- tinct T-ALL subtypes,132–134 others remain reluctant.135,136 In T cell ALL represents an heterogeneous subgroup of ALL in that respect, Schott et al137 reported a better outcome for which a large number of distinct cytogenetic abnormalities patients with T cell ALL with TCR-␥/␦ expression. TAL1 gene have been identified.6,29,117,118 This disease predominantly rearrangements seem to be restricted to TCR-␥/␦ T cell affects boys of older age who present with hyperleukocytosis ALL.136,138 The role and relationship of TAL1 and of TCR gene and extramedullary disease.119,120 Cytogenetically, clonal rearrangements in both diagnosis and monitoring of T cell ALL abnormalities are less commonly found than in B precursor thus requires further investigation. ALL cases, and hyperdiploidy is rare.30,31,117,118 There is a sig- nificant overlap in the cytogenetic abnormalities identified in T cell ALL and T cell lymphoblastic lymphomas, which there- ALL with 9p abnormalities and deletion of fore may represent two different forms of the same disease.118 p16INK4a/MTS1 and p15INK4b/MTS2 genes The most common translocations, t(11;14)(p13;q11), t(10;14)(q24;q11), t(8;14)(q24;q11), t(7;11)(q35;p13) and Cytogenetic abnormalities of the short arm of chromosome 9 t(7;14)(p15;q11), involve specific chromosome breakpoints (9p) are observed in 7–12% of childhood ALL cases.139–142 Review JA Martinez-Climent 2005 They include interstitial deletions, reciprocal translocations, geneous population of children encompassing distinct dicentric chromosomes and complete losses of 9p, all of them immunological and cytogenetic variations of ALL. Further resulting in deletions of bands 9p21–22.16 Children with ALL studies are needed to clarify whether these leukemias should and 9p abnormalities tend to have leukemias with T cell be considered as a distinct clinical–biological subgroup and phenotype, clinical lymphomatous features, and a worse prog- what the prognostic significance of the deletions is. nosis than other subgrups of ALL.140,142 However, several authors failed to confirm these observations.141,143 The inter- feron-alpha gene cluster (IFNA) and interferon beta-1 gene Other recurrent cytogenetic abnormalities (IFNB1) reside within the commonly deleted region on 9p.144 More recently, the two cycling-dependent kinase inhibitors Rare cases of ALL are characterized by specific chromosomal p16INK4a/MTS1 and p15INK4b/MTS2 genes were also localized abnormalities, such as precursor B cell ALL with hypereosino- within the deleted band 9p21 in several solid tumors and philia and t(5;14)(q31;q32).6,16,162 This syndrome occurs in hematological neoplasias, particularly in ALL.145–148 These less than 1% of ALL, and involves the interleukin-3 gene (IL- linked genes are inactivated by either homo- or hemyzygous 3) on and the IGH gene on chromosome 14.163 deletions in 28–61% of childhood ALL70,149–157 (Table 3). In Abnormalities of the long arm of chromosome 6 were ident- adult and pediatric ALLs of T cell lineage, p16/p15 deletions ified in 11% of childhood ALL, mostly deletions from 6q15 are detected more frequently (up to 80%) than in B precursor to 6q21.164 These ALL, however, did not display a peculiar ALL.149,151,153,155–159 Loss of function of the genes results immunophenotype, were frequently associated with other almost exclusively from deletions rather than point major recurrent cytogenetic abnormalities, and had a clinical mutations.151 Childhood ALL samples with p16INK4a/p15INK4b outcome similar to all other ALL cases.6,16,164 deletions often display abnormalities of 9p (31 of 80 cases included in three series, 39%). Even more often, however, kar- yotypes are normal or disclose nonspecific abnormali- Acute myeloid leukemia ties.149,155,156 p16INK4a/p15INK4b deletions have also been identified in t(4;11) or t(9;22) leukemias149,151,155,160,161 but Myeloid cancers represent 15–20% of all childhood hematol- not in the t(1;19) ALL group.160 ogical neoplasias, and acute myeloid leukemia (AML) Children with ALL and p16INK4a/p15INK4b deletions present accounts for 95% of cases.1,165 The prognosis of AML has not with aggressive clinical and biological features such as hyper- improved as it has for children with ALL. Despite the fact that leukocytosis,149,153,156 nonhyperdyploid karyotypes or DNA up to 85% of pediatric AML patients achieve remission, most index Ͻ1.16151,153,155,156,160 and older age.153 Survival rates of them relapse and more than 30% of childhood deaths from seem to be superior for children without p15/p16 deletions. leukemia are the consequence of AML.1,165–167 Allogeneic Heyman et al149,150 reported that children with p15/p16 BMT is indicated in those children with an HLA-identical sib- homozygous deletion did worse than those with non-deleted ling, resulting in cure rates of 50–55%.1,165–170 However, less and hemyzygously deleted lesions grouped together. How- than 40% of children treated with either autologous transplan- ever, Rubnitz et al70 did not confirm the superior outcome tation or intensive chemotherapy will be long-term sur- for children with ALL without homozygous p16 deletion in a vivors.170,171 These results have prompted researchers to uniformly treated group. In conclusion, deletion of candidate investigate disease features with prognostic significance in an tumor-suppressor genes p16INK4a/p15INK4b, the most common attempt prospectively to identify patients who will not respond genetic abnormality in pediatric ALL, is detected in a hetero- to therapy or will relapse.172,173

Table 3 Deletion of P16 gene in childhood acute lymphoblastic leukemia

Author/Ref. Cases with P16 deletion/total of cases Type of Genetic features of cases with Clinical and prognostic in deletion P16 deletion significance HH/Hh ALL (%) T-ALL B-ALL

Heyman149 36/79 (45) 11/13 18/49a 24/12 5 of 5 with 9p abnormality High WBC (P Ͻ 0.01), not Rasool150 9 hyperdiploidy, 1 del(11q23) differences in age, sex. Poor prognosis (P = 0.01) Ohnishi151,160 35/116 (30) 22/56 13/60 22/13 2 t(9;22), no in t(1;19) No differences in sex, age, WBC Similar clinical outcome Takeuchi153 38/103 (37) 19/22 19/81 29/9 DNA index Ͻ1.16 Older age (P = 0.03), high WBC (P = 0.009) Mediastinal mass (P Ͻ 0.001) Similar 5 year EFS Rubnitz70 36/155 (23)b 14/23 22/133 36/NR DNA index Ͻ1.16 Similar 5 year CCR (P = 0.44) Okuda155 23/43 (53) 10/11 13/32 16/7 18 of 20 cases with 9p abn. No differences in sex, age, WBC 3dic(9;12)/dic(7;9),2t(9;22) Poor 5 year EFS: 40 vs 69 (P = 1 t(4;11), no hyperdiploidy 0.095) Guidal Giroux156 21/46 (45) 7/7 14/39 15/6 8 of 8 with 9p abnormality Frequent elapses (9/21 vs 3/25) aThe remaining 17 leukemias were classified as biphenotypic or were unclassified. bHomozygous deletion. NR, not reported; HH/Hh, homozygous/hemyzygous deletion of p16; CCR, continuous complete remission; EFS, event-free survival. Review JA Martinez-Climent 2006 Cytogenetic analysis reveals clonal abnormalities in 80– Numerical abnormalities 85% of children with AML.18,19,174,175 These studies have played an important role in refining the FAB classification of Most hyperdiploid cases of AML have only one or two extra AML, either by identifying structural chromosomal abnormali- chromosomes.2 The more frequent gain is 8, reported ties correlated with distinct FAB subtypes, or by separating in 5–10% of pediatric AMLs; was found in 54 of similar morphological leukemia subgroups such as AML-M2 666 cases with adequate cytogenetic analysis included in five with or without t(8;21).3,8,176 The major phenotype-specific independent series.18–20,183,184 In patients with Down syn- chromosomal abnormalities are detected in 50–60% of all drome and AML the incidence is higher.185,186 This anomaly childhood cases (Table 4). Complementary molecular tech- has been described in all FAB subgroups and is not associated niques identify otherwise undetected rearrangements in a few with any one in particular; in more than half of cases +8is patients with apparently normal karyotypes, and therefore present with other recurrent abnormalities.4 Trisomy 8 has not assign them into the well-defined morphological sub- been found to influence leukemia prognosis except when it groups.44,177–179 However, following this scheme one-third of appears as a secondary karyotypic change in aggressive AML have non-specific clonal karyotypes unsuitable to categ- cases.107 The extra , however, is useful for orize these leukemias. Recently, the importance of cytog- monitoring the disease with FISH.187,188 enetic analysis in myeloid leukemias is emphasized by A gain of other chromosomes include: trisomy 21, which is Head177 by introducing a novel attractive revised classification detected in children with AML without , and of AML, which appears to be of more clinical relevance than in some cases, associates with a constitutional +21 in children the FAB classification. with Down syndrome;185,186,189 trisomy 22, which strongly Clinical significance of the cytogenetic stratification of correlates with M4Eo with inv(16);190 and trisomy 4, a nonspe- childhood AML has been studied in three retrospective ser- cific finding in less than 1% of AML cases.173,191 ies.19,174,175 Investigators have found different outcomes in the Partial or complete loss of chromosome 7 is frequent in distinct genetic subgroups, thus suggesting that patients with myeloid neoplasms.192,193 Leukemias with or poor prognosis karyotypes should be treated with more deletion of the long arm of chromosome 7 (7q) are grouped aggressive or novel therapies.180 The role of BMT in children together, as both abnormalities lead to the loss of a tumor(s) with favorable cytogenetic abnormalities such as inv(16), suppressor(s) gene(s) located on 7q which affect a pluripotent t(8;21) or t(15;17), is still to be defined, as these patients may hematopoietic progenitor cell.194–196 Two different regions are not require a transplant in first remission.181 Cooperative and commonly deleted in myeloid neoplasms: 7q22 and 7q32, the prospective clinical studies involving the application of mod- latter associated with a worse prognosis.193,197,198 De novo ern genetic methods will be essential to subclassify all chil- monosomy 7/del(7q) occurs in several childhood myeloid dis- dren with AML into clinical–biological entities which share orders, including AML and MDS.199 In AML, −7/del(7q) is similar responses to treatment. This may subsequently allow detected in about 5–7% of cases.18,19,183,184,199,200 In a review individualized therapies to be tailored and also residual leuke- of 31 children and adolescents with de novo AML and mia to be monitored during treatment and follow- −7/del(7q), the median age was 10.5 years and the sex ratio up.1,2,4,181,182 M:F was 2.2:1; leukemias were not associated with any parti-

Table 4 Recurrent chromosomal abnormalities in childhood acute myeloid leukemia

Cytogenetic Rearranged FAB Incidence Associated features abnormality genes subtype %

t(8;21) ETO-AML1 M2 10–15 old age, males, extramedullar tumors, high CR, intermediate prognosis t(15;17) PML-RARA M3 8–15 old age, females, clotting abnormalities, response to ATRA, favorable prognosis inv(16),t(16;16) MYH11-CBFB M4Eo 6–11 CNS disease (?), high WBC (?), favorable prognosis t(9;11) AF9-MLL M5a 8–10 young age, no aggressive features, response to VP-16, favorable prognosis t(11q23)a MLL-othersa M4/M5,t-AMLb 8–10 infants, high WBC, CNS and skin disease, organomegaly, dismal outcome del(7q),−7?c AML,t-AMLb 5–7 frequent MDS, bacterial infection, low CR, poor outcome t(1;22) ? M7 2–3 infants without Down syndrome, organomegaly, poor outcome t(6;9) DEK-CAN M2/M4d 1 young adults, frequent MDS and basophilia, poor outcome t(8;16) MOZ-CBP M4/M5e 1 infants or young adults, organomegaly, skin disease, poor outcome +8 ? AML 5–9 nonspecific finding, associated with other cytogenetic abnormalities

t-AML, therapy-related acute myeloid leukemia. aAll other 11q23 translocations involving MLL and distinct partner genes. bIncidence of t(11q23) and del(7q) is higher in t-AML. cOne or more tumor suppressor genes. dAML with basophilia. eAML with erythrophagocytosis. Review JA Martinez-Climent 2007 cular FAB subgroup, although −7/del(7q) was more frequent in long-term remission.182,222–224 However, two recent reports in M4 and M6, and many cases were preceded by myelodys- support the value of serial quantification of AML1-ETO tran- plasia.199 Clinical findings include bacterial infections and scripts to monitor disease progression and predict relapse in prolonged marrow aplasia after chemotherapy.19,174,199 Uni- patients with AML and t(8;21).225,226 formly, children have very low remission and survival rates. Only a few long-term survivors have been reported following Acute promyelocytic leukemia (APL) AML-M3 and the allogeneic BMT, which appears to be the only curative option t(15;17)(q22;q11.2) currently available.19,174,199 Loss of a sex chromosome, X or Y, is much less common Childhood APL represents 3–10% of cases in several in young patients than in adults. In children, most cases are series.18–20,183,227–230 However, the incidence of APL in associated with a t(8;21), frequently representing secondary Italy, South American countries and Spain appears to be karyotypic events.201 It is remarkable that monosomy 5/del(5q) higher.231–233 The characteristic t(15;17) is found in virtually is rarely observed in childhood de novo AML or MDS, while all cases of APL, including microgranular and other vari- being a common finding in adults with these disorders.1,192 ants.5,234,235 Moreover, this translocation is absent in patients These findings are suggestive of a distinct pathogenesis of with any other type of leukemia or solid tumor, with the these leukemias in adults vs children.177 exception of CML in blasts crisis and M3 morphology.2,233,234 Additional genetic alterations including trisomy 8 and, less commonly, iso(17q), are seen in up to one-third of cases and Structural abnormalities: correlation with FAB subgroups are associated with worse prognosis.235,236 Variant translo- cations are rare in APL.237 t(8;21)(q22;q22) and AML-M2 Clinically, children with APL are predominantly of older age and female sex. They presented with low leukocyte count The t(8;21) is the most common structural abnormality in and frequent clotting abnormalities.19,174,227–230 When childhood AML, almost always associated with AML-M2.202 In exposed to therapy protocols designed for AML, more than seven series including 769 cases of AML, 108 children (14%) one-third of children with APL died during induction, showed a t(8;21): 89 were M2 (82%), 13 were M1, and only although when in remission they had prolonged six had other phenotypes.18–20,184,200,203,204 These 89 cases responses.19,174,183,203,230,231 All-trans retinoic acid (ATRA) is at represented 38% of all M2 cases included in these series. present used as induction therapy along with chemotherapy, Cytogenetic variants of t(8;21) were detected in 1.1% of 638 achieving complete remission in more than 80% of cases of childhood AML in a collaborative study.205 t(8;21) is patients.231,233,238–242 Post-remission chemotherapy is neces- associated with loss of the sex chromosomes in more than sary, and long-term survival is obtained in more than 70% of 60% of patients.201,205 This proportion is lower in childhood children and adults.233,240–242 leukemias, ranging from 25 to 55%. Deletion of the long arm The t(15;17) fuses the RARA gene on to of chromosome 9 occurs non-randomly in t(8;21) AML leuke- the PML gene on .243–246 The chromosome 15 mias, and was recently linked with poor outcome.201,206 breakpoint falls within three different breakpoint cluster The presence of t(8;21) and its variants identifies a subset regions of the PML gene in intron 6 (bcr1, 70% of cases), of AML-M2 which can be distinguished morphologically from intron 3 (bcr3, 20%) and exon 6 (bcr2, 10%). The chromo- other M2 cases.207–209 Also, a distinctive immunophenotypic some 17 breakpoint occurs almost always in intron 2 within pattern with expression of myeloid markers as well as CD19 the locus that encodes for the retinoic acid receptor alpha and CD56, but lack of T cell antigens, has been gene (RARA). The PML/RARA fusion gene is actively tran- described.210,211 Clinically, children are older, predominantly scribed as a chimeric mRNA detectable in 100% of APL male, and have a high incidence of extramedullary tumor cases.247 Most variant translocations of t(15;17) usually masses.204,209,212,213 They also experience high remission and involve the PML and RARA genes.237 However, a subset of survival rates,183,203,204 as compared to other AML-M2 APLs (often with atypical morphology) exhibits variant translo- cases184 or to all AML cases lacking t(8;21).200,204 However, cations; the more significant is t(11;17), which fuses the RARA the better clinical outcome was not confirmed to be so favor- gene to a novel gene called PLZF, defining a distinctive form able in two series of pediatric AML19,174 as compared to adult of leukemia which fails to respond to retinoic treatment.248,249 AML.173,209,214–216 In our experience, nine patients with t(8;21) Based on the clinical response to ATRA and the insight into included in a series of 115 children with AML had a poor the molecular function of the fusion proteins, it has been sug- outcome (only one was alive at 3 years from diagnosis).19 Four ested that disturbances of the RARA receptor gene play a had an additional del(9q) and three others initially presented major role in the pathogenesis of APL. Recently, Vyas et al250 with central nervous system disease; both features are associa- demonstrated the response to ATRA to be associated with ted with inferior outcomes in AML and then may contribute maturation, subsequent loss of the mature leukemic elements, to the poor course of the disease.172,201 In a recent series and preferential regeneration of normal hematopoietic encompassing 220 children with AML, 36 exhibited t(8;21) elements in APL patients. and did not do better than all the other patients.175 It remains The detection of the PML/RARA transcripts by RT-PCR pro- to be defined whether children with AML and t(8;21) should vides a rapid and extremely sensitive tool to diagnose and receive allogeneic BMT in first complete remission, provided monitor children with APL.251–253 Similar results have been a donor is available, but for now it seems a rational option.217 obtained using FISH.254 Prolonged survival is associated with At a molecular level, the t(8;21) interrupts two genes, AML1 the absence of the PML/RARA fusion product, and a positive on 21q22 and ETO on 8q22.218–220 Molecular techniques RT-PCR after previous molecular remission predicts early allow for the detection of the AML-ETO fusion product in all relapse. Accurate genetic diagnosis of APL appears essential patients with t(8;21).220,221 These tests have not been useful as ATRA therapy may only induce remission in leukemic cells for monitoring residual disease, as AML1-ETO transcripts were harboring t(15;17) or variant translocations resulting in PML- also detected when examining peripheral blood of patients RARA transcripts.181,238,239,252 Review JA Martinez-Climent 2008 Acute myelomonocytic and monocytic leukemia cal translocations involving band 11q23 affect 5–8% of chil- (AML-M4 and M5) dren with ALL, with t(4;11) and t(11;19) predominating (see above). In children with AML, 11q23 abnormalities are found Inversion of chromosome 16 and AMMoL-M4: The in 5 to 18% of cases.18,183,184,200,203 In five large series involv- inv(16)(p13q22), and its variant t(16;16)(p13;q22), are non- ing 577 children with AML, 85 (15%) revealed cytogenetic randomly associated with acute myelomonocytic leukemia rearrangements of band 11q23.18–20,184,200 In a recent review, with abnormal eosinophils (AMoL-M4Eo).255 Leukemias with 17% of 220 children with AML were reported to have 11q23 inv(16) consistently display eosinophils with altered mor- abnormalities.175 This proportion is raised to near 20% when phology and ultrastructure which allows them to be dis- complementary FISH and molecular analysis had been instru- tinguished from other myelomonocytic leukemias.207,255 The mental for diagnosis.44,179 t(9;11), t(6;11) and t(11;19) are the frequency of inv(16) in children with AML ranges from 6 to most common translocations, although more than 15 other 11%, and is seen in 19–36% of all M4 cases.18–20 The vast genetic alterations are known.40,41,272 All of them involve the majority of leukemias with inv(16) are classified as same gene, MLL, which is found rearranged in about 95% of M4Eo;2,19,107,255 some cases, however, have other phenotypes all t(11q23) by Southern blotting (Figure 4).42,43 but many of them exhibit bone marrow eosinophilia and/or Myeloid leukemias with t(11q23) are commonly of myelo- abnormal eosinophils.18,20,256–258 Moreover, inv(16) AML pro- monocytic or monoblastic lineage.1,4,273 In a series of 115 duces a specific immunophenotype accompanied by CD2 children with AML, 36 showed M4 or M5 leukemias, not expression.259 Trisomy 22, otherwise a very rare finding in including nine others who had M4Eo-inv(16). Eighteen of myeloid cancers, is non-randomly associated with inv(16).190 these 36 patients had t(11q23): 14 of 20 M5 cases (70%), and As in other cytogenetic subgroups, an extra chromosome 8 is four of 16 M4 cases (25%).179 Moreover, only a few AMLs sometimes present with no specific significance. Cases with with translocations or inversions of 11q23 exhibit phenotypes del(7q) have been also reported.107,255 Variant abnormalities other than M4-M5.18,20,179 As happens in ALL, 50–70% of of inv(16) are extremely rare. infants with AML have 11q23 abnormalities.40,41,44,273 In a Children with inv(16) are generally undistinguishable from similar retrospective study of 65 adults, 11q23/MLL rearrange- the entire group by clinical data,18,174,200 although one clinical ment was found in 11 of 40 M4 cases (28%) and in only four study characterized them as being older and presenting with of 25 M5 cases (8%).274 Frequently, AML with t(11q23) hyperleukocytosis.19 Remarkably, Raimondi and Kalwinsky174 express lymphoid antigens, and bi-phenotypic leukemias reported a high incidence of CNS disease at diagnosis (eight often have abnormalities of band 11q23.136,275–277 Taken of 15 children with inv(16)) and at relapse (three of eight), together, these observations suggest that 11q23 rearrange- data shown previously in adults.260 However, frequent CNS ments affect a pluripotential progenitor cell capable of both involvement was not confirmed in other pediatric series.19,184 myeloid or lymphoid differentiation.1,40,41 Moreover, t(11q23) Effective CNS prophylaxis therapy thus might be necesary in is common in therapy-related leukemias, especially in chil- this group of patients.174 dren previously treated for ALL with agents that bind to DNA- Prognosis for adult patients with AML-M4Eo and inv(16) is topoisomerase II.278–281 better when compared to other subgroups of Of 59 children with AML and t(11q23) included in three AML.173,215,216,261 In children, complete remission was achi- series, 28 (47%) had a t(9;11)(p22;q23). All were classified eved in almost all patients in four clinical trials.19,174,175,183 as M5a with expression of myeloid and immature monocytic However, in the St Jude’s series survival for the inv(16) sub- markers.18,19,184 These cases, however, cannot be morphologi- group was not superior with respect to others, probably due cally distinguished from other M5 without t(9;11). The remain- to the high incidence of CNS disease.174 In our experience, ing children with other 11q23 abnormalities represent a het- children with AML and inv(16) have a better EFS when com- erogeneous population with different translocations such as pared either to all other AML-M4 leukemia or to the remaining t(6;11), t(11;19), t(10;11) and t(11;17).4,18–20,184 Children with patients,19 thus confirming results of the adult series. t(9;11) are clinically indistinguishable from other patients with Cloning of the inv(16) breakpoints identified two genes, CBFB on 16q and MYH11 on 16p.262,263 The fusion product CBFB-MYH11 was detected in all but two patients in a series including 37 children and adults with inv(16).264 The corre- sponding CBFB-MYH11 fusion protein was detected in 20 of 22 cases of inv(16).265 However, chimeric mRNAs are hetero- geneous because of the various breakpoints observed within the MYH11 gene.263,266,267 Also, it is still unknown whether identification of the fusion gene product predicts relapse.181,182,265 Recently, Kuss et al268 reported that in inv(16) leukemias the multidrug resistance protein gene MRP is deleted, which may contribute to the chemosensitivity and subsequently favorable prognosis of these leukemias. CBFB- MYH11 fusion transcripts were detected in about 10% of AML-M4 cases without eosinophilic abnormalities269 and in 6% of AML with phenotypes other than M4.270 For that rea- son, the use of FISH and RT-PCR is of special value as subtle Figure 4 Molecular analysis for the MLL gene in childhood leuke- chromosome 16 abnormalities are difficult to detect with mias. Results of Southern blot analysis of DNA from infants with ALL conventional cytogenetics.270,271 and AML and a normal karyotype by cytogenetic analysis. The DNA was digested with BamHI (left) and HindIII (right). In samples from patients shown in lanes 1, 2, 3 and 5, a single germline band was detected. Lane 4 contains DNA from a patient with ALL, who had a Abnormalities of band 11q23 and the MLL gene: Recipro- single faint rearranged band. Review JA Martinez-Climent 2009 M5 leukemias lacking t(11q23). In contrast, children with leukemias), and older children (five older than 13 years, and other translocations of 11q23 display aggressive features such one aged 8 years). Ten cases were classified as M5 and four as hyperleukocytosis, CNS disease, organomegaly and skin as M4, and erythrophagocytosis was demonstrated in 10 of involvement.19,174 Myeloid leukemias with t(11q23) have a 13 cases with available data. Clinically, hepatosplenomegaly poor outcome in most adult series,173,215,216,282 although this and lymphadenopathy were present in most of the cases prognostic significance may be absent in elderly patients.274 (seven of 10), and skin involvement was also frequent (four of In two retrospective series of AML, survival for children with 10). CNS disease was not reported. As in adult cases, survival t(9;11) was superior when compared to patients with other was poor with only four children surviving more than 6 t(11q23), who all had a dismal outcome.19,174,179 These sur- months.19,287–296 prising results were confirmed by Leblanc et al,175 reporting Recently, Borrow et al297 cloned the t(8;16) breakpoint. It a better outcome in 16 children with t(9;11) than in 21 cases involves a gene for acetyltransferase at 8p11 (MOZ) fused to with other t(11q23) abnormalities (Table 5). Why patients with a gene for a CREB binding protein CBP at 16p13. With the t(9;11) do better than those with other t(11q23), all of which availability of sequencing data, molecular recognition and involve the MLL gene, is unknown. It may be explained in monitoring of these leukemias is possible. part by: (1) the impact of the other partner gene in the translo- cation;40,41 (2) the good response of M5-t(9;11) leukemias to VP-16;4,283 and (3) the lower incidence of hyperleukocytosis, t(6;9)(p23;q34): The translocation t(6;9) was first skin and CNS involvement in the t(9;11) group.19,174 These described to be associated with AML by Rowley et al298 in findings should translate into therapeutic strategies tailored for 1976. Less than 60 cases have been reported to date, rep- these two subgroups of childhood AML. The favorable prog- resenting 0.5–4% of all AMLs.299,300 Patients are younger than nostic significance of t(9;11) has yet to be confirmed in adults, in other types of leukemia (median age, 28 years). They have where t(9;11) is less common. AML-M2 or M4, often associated with bone marrow baso- The combination of cytogenetic, FISH, and molecular philia and preceding MDS.299 Only 20 reported cases were analysis provides a highly sensitive strategy for the detection aged less than 20 years, most of them young adults.19,20,300–308 of 11q23/MLL gene rearrangements in childhood leukemias, Ten had M4, eight M2, one M1 leukemia and one MDS. A which is essential as the MLL status is such a powerful prog- preceding MDS was described in all eight cases with available nostic determinant (Figures 2 and 3).40,44,179,284,285 Despite the information, and bone marrow basophilia in only three of 17 heterogeneity of genes located on partner chromosomes fused patients. Prognosis is uniformly poor, but it seems slightly to MLL, Southern blotting and RT-PCR are capable of better in young adults.300 detecting 100 and 90% of these MLL rearrangements, respect- Molecular analysis of t(6;9) has shown that the breakpoint ively. Screening for multiple translocations in a single PCR in 9q34 is different than the one identified in the typical reaction will be of clinical importance once avail- t(9;22).309 The two genes involved in the t(6;9), DEK on 6p23 able.12,40,41,43,46,286 and CAN on 9q34, fuse in a chimeric DEK-CAN mRNA which is useful for diagnosis and monitoring of the disease.300,310,311 t(8;16)(p11;p13) and AML M4-M5: t(8;16) is non-ran- domly associated with AML-M4 and M5 with erythrophago- Erythroleukemia or AML-M6 cytosis.287–290 Its incidence is very low (0.33–2.2% of all AML cases).289,291 A few cases with similar clinical–biological fea- This form of leukemia represents only 1–2% of all childhood tures display variants of t(8;16), which always involve the AML cases.167,312 In a series by Malkin et al312 including 10 8p11 breakpoint.291 Fourteen patients aged less than 20 years cases and reviewing 14 more, children had a median age of with leukemia and t(8;16) have been reported.18,19,287–296 They 4.7 years, male predominance, frequent Down syndrome, and can be separated into two subgroups according to age at diag- a poor response to chemotherapy with frequent relapses. nosis: infants (eight cases, including four congenital Cytogenetically, two major subgroups of AML-M6 can be dis-

Table 5 Clinical response of children with acute myeloid leukemia according to cytogenetic subgroup

Cytogenetic subgroup Patients in CR/total of patientsa (%) Estimates (%) ofc

EFS 3 years19 DFS 2 years174 DFS 4 years175 (n = 115)b (n = 121) (n = 220) t(8;21) 53/59 (90) 11 50 53 t(15;17) 21/30 (70) 44 75 51 inv(16) 40/42 (95) 50 39 68 t(9;11) 31/35 (89) 56 75 77 t(11q23) 37/40 (92.5) 11 0 21 Miscellaneous 63/85 (74) 21 35 37 Normal 37/40 (92.5) 16 41 46 Total 382/450 (85) 26 35 51 aAll 450 patients included in Refs 19, 174 and 175. b109 patients with follow-up. cEstimates of survival as reported in the series. Underlined numbers indicate P Ͻ 0.05. Miscellaneous subgroup represents all patients with clonal abnormalities not included in the other subgroups. Review JA Martinez-Climent 2010 tinguished: (1) patients with complex karyotypes, generally an overall frequency of 24% of all childhood AML-M7 with abnormalities of chromosomes 5 and 7 (complete losses, cases.330 There are no data available regarding the prognostic deletions or balanced translocations), who share biological influence of acquired +21 in AML. and clinical features with therapy-related AML, including a poor prognosis; and (2) patients with simple or not detectable cytogenetic abnormalities, who commonly have a de novo t(1;22)(p13;q13) and AML-M7: The 1;22 translocation has AML-M6 picture with more favorable prognosis.313,314 Of the been described exclusively in very young children with AML- 42 children and adolescents with AML-M6 and cytogenetic M7, representing approximately one-third of childhood AML- analysis previously reported,19,20,200,204,312,314–325 12 had a M7 (Figure 1b).338–345 Common features present in 24 patients normal karyotype at diagnosis (29%). This percentage is reported to date19,338–344 are median age of 6 months, absence higher compared with nine of 78 cases (12%) included in of Down syndrome, transient leukemia or myelodysplasia and three major adult series.313,314,319 Moreover, complex kary- massive organomegaly. Several cases were misdiagnosed as otypes were reported in 33% of children vs 80% of adult solid tumors prior to cytogenetic analysis.19,344 A hyperdiploid cases. The most common karyotypic change was monosomy karyotype was seen in 25% of cases with t(1;22).345 Prognosis 7/del(7q) (nine of 42 cases), but in contrast to adult AML-M6, appears to be very poor,345 although several patients were it was present as a single cytogenetic abnormality in most long-term survivors following autologous BMT.19,339,340,344 patients. Other findings included of chromosomes 8 Cloning of genes involved in t(1;22) is important and might and 21 (six cases each), whereas deletion of 5q, common in help to identify more patients with this abnormality. adults, was absent. Five of 42 childhood cases had Down syndrome. Therefore, most children with AML-M6 can be ascribed cytogenetically to the group characterized by single AML-M7 with abnormalities of bands 3q21 and 3q27, and abnormalities, frequently −7/del(7q) or normal karyotypes, monosomy 7/del 7q: These karyotypic changes are rela- and a somewhat better prognosis. tively common in adult AML-M7, but only a few cases have been described in children, most of them young ado- lescents.330 As in older patients, most children with 3q21– Acute megakaryoblastic leukemia or AML-M7 3q26 abnormalities suffered from myeloid malignancy, pre- dominantly AML-M7 with trilineage myelodysplasia, and AML-M7 comprises 3–5% of all childhood AML and about experienced poor prognosis.346–349 20% of infant leukemias.1,165,326 Detection of platelet peroxi- dase (PPO) activity by electron microscopy and recognition of platelet glycoprotein antigens has facilitated the diagnosis The myelodysplastic syndromes (MDS) of AML-M7, resulting in an increase in its reported fre- quency.326–329 Children with AML-M7 can be classified MDS are very rare in children, representing 3% or less of all according to the cytogenetic analysis into four different sub- hematopoietic malignancies.350–354 More than 80% of child- groups.330 hood MDS belong, according to the FAB criteria, in the more advanced stages, namely refractory anemia (RA) with excess of blasts (RAEB), RA with excess of blasts in transformation AML-M7 and Down syndrome (DS): DS is associated with (RAEB-t), and chronic myelomonocytic leukemia (CMML), a 20-fold increased risk of developing leukemia during child- whereas RA and RA with ringed sideroblasts (RARS) are much hood, both ALL and AML.185,331 Unique features of AML in less common than in adults.350–362 Predisposing conditions for DS patients are: a 500-fold higher incidence of AML-M7; a childhood MDS include constitutional chromosomal disorders frequent presentation with myelodysplasia or transient leuke- (Down syndrome), neurofibromatosis, Schwachman syn- mia; and frequent dyserythropoiesis in bone marrow with drome, Kostmann’s neutropenia and Fanconi’s ane- coexpression of T cell antigen CD7 on blast cells.331,332 Forty mia.350,351,358 Familial occurrence of MDS, mostly associated children with DS have been identified among 633 patients in with monosomy 7, has been reported, and clinicians should the cooperative BFM studies for AML.332 Advances in diagnos- always consider the possibility that a child who presents with tic methods permitted the classification of almost all myeloid MDS or AML and monosomy 7 may have a familial dis- leukemias in DS as AML-M7.185,186,331–333 On the other hand, order.195,196 half of children with M7 leukemias have DS.185,326,330 Cytogenetic analyses are essential for the evaluation of a Although no specific hallmarks were identified, cytogenetic child with proven or suspected MDS.351 Recently, Chan et analysis had shown absence of t(1;22), frequent trisomy 8, and al362 have emphasized the value of chromosome studies to less commonly, trisomies 1 and 21.185,186,326,328,330–334 The differentiate childhood MDS from AML with low blast count, presence of an extra copy of in transient the latter having a better response to therapy. In three reviews megakaryoblastic leukemia seen in infants with DS, which in including 137 children with MDS, 88 (64%) had an abnormal a quarter of cases will finally develop AML-M7, is likely to be karyotype at diagnosis,20,350,358 a higher incidence than in involved in the pathogenesis of transient leukemia.164,166,331 adult MDS.359,360 Monosomy 7/del(7q) was the most frequent Children with AML and DS have a markedly superior outcome abnormality, found in 45% of abnormal cases. More signifi- compared to those without DS, especially with regimens con- cant is that abnormalities of chromosome 7 are not part of the taining high-dose cytarabine.166,332,335–337 complex karyotypes commonly seen in adults, but are found as single chromosomal changes.192,199 In a recent review from the EWOG-MDS of 110 children with myeloid disorders and AML-M7 and acquired trisomy 21: In a review, acquired monosomy 7/del(7q), 79 had MDS and 32 had AML.363 trisomy 21 was found in eight of 68 children suffering from Monosomy 7 predominated in MDS cases, mainly as a single AML-M7 without DS.330 Trisomy 21 was also found in four abnormality, whereas del(7q) was more frequent in AML. In patients with t(1;22), and in six children with DS, representing our experience, 12 cases of childhood MDS were seen at La Review JA Martinez-Climent ´ 2011 Fe Children’s Hospital in Valencia, Spain between 1982 and treated with alkylating agents. These secondary leukemias 1992; five had a normal karyotype, including one with a con- present with features of trilineage myelodysplasia which often stitutional t(13;14), four displayed monosomy 7, one of them evolve to AML. Twenty cases disclosed 11q23 abnormalities included a complex karyotype, one disclosed a del(5q) with (40%), and virtually all were exposed previously to epipodo- other anomalies, and two showed other abnormalities (JM-C, phyllotoxins and/or anthracyclines as part of treatment for ALL unpublished). Other cytogenetic abnormalities observed in or solid tumors. No signs of marrow dysplasia were observed MDS include trisomies of chromosomes 8, 9 and 19, del(12p), in them. Prognosis for these two subgroups of secondary del(17p), and much less frequently than in adults, deletion myeloid disorders is very poor despite all the available of 5q.192,350,351,358 therapeutic options.278–281,368 The monosomy 7 syndrome (M7S), a form of MDS with bone marrow dysplasia, bacterial infection and skin rash, 364–366 affects almost exclusive young children. The juvenile Acknowledgements chronic myelomonocytic leukemia (JCML) is diagnosed in children with a marrow picture resembling adult CMML, This work was supported in part by the Center for Cytometry increased fetal hemoglobin level and lack of t(9;22)/BCR-ABL 199,358 and Cytogenetics from the University of Valencia, and by rearrangement. M7S and JCML share many clinical and Grants No. 93/5308-BAE and 94/5528-BAE from the Spanish epidemiological features, and there is controversy about 199,350,351,358,366 Ministry of Health (Fondo de investigaciones Sanitarias). I am whether they represent distinct disorders. For indebted to Professors Janet D Rowley (University of Chicago) ´ example, in a review of 46 children with JCML, 11 (24%) and Javier Garcıa-Conde (University of Valencia) for their showed monosomy 7 in the bone marrow.199 According to an 199 invaluable comments and support during the preparation of excellent review by Luna-Fineman et al, M7S is one of the this article. entities associated with chromosome 7 loss whereas JCML is a myeloproliferative disorder associated with monosomy 7 in 6–24% of cases. In contrast, other authors do not delineate M7S as an independent entity as such cases either fall into References JCML or can be otherwise classified according to the FAB 351,354,355 1 Pui C-H. Childhood leukemias. New Engl J Med 1995; 332: criteria. 1618–1630. Rapid transformation into AML despite therapy is a general 2 Rowley JD. Recurring chromosome abnormalities in leukemia rule for all preleukemic states with monosomy 7, and survival and lymphoma. 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