Case Report Journal of International Medical Research 2014, Vol. 42(6) 1363–1373 Acute promyelocytic ! The Author(s) 2014 Reprints and permissions: leukaemia with a PML-RARA sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0300060514540630 insertional translocation and imr.sagepub.com a 21 abnormality in XYY : Case report

Yi He*, Xudong Li*, Dongning Wang, Erhong Zhang, Yuan Hu, Wenwen Wang, Renwei Huang and Ruozhi Xiao

Abstract The concomitant presence of the XYY syndrome with haematological malignancies is rare. This report presents a case of acute promyelocytic leukaemia (APL) with the promyelocytic leukaemia- retinoic acid receptor alpha (PML-RARA) gene insertional translocation and a abnormality in a 29-year-old XYY male patient. analysis revealed an abnormal karyotype of 47,XYY [14]/46,XYY,–21[16]. Fluorescence in situ hybridization and reverse transcription– polymerase chain reaction analysis showed the existence of a PML-RARA fusion gene. The patient was treated by all-trans retinoic acid (ATRA) and chemotherapy. Laboratory results revealed that the coagulopathy improved and the patient achieved complete remission, based on bone-marrow morphology. The patient then received sequential monthly therapy using arsenic trioxide, followed by ATRA, followed by chemotherapy; he has survived disease-free for 36 months. Our findings suggest that the additional chromosomal abnormalities involving the and chromosome 21 did not affect the of APL, and that the sequential treatment strategy had a good clinical effect without being associated with severe side-effects.

Keywords Acute promyelocytic leukaemia, XYY syndrome, additional chromosomal abnormalities, PML-RARA insertional translocation, all-trans retinoic acid

Date received: 19 February 2014; accepted: 28 May 2014 *These authors contributed equally to this work and are co-first authors.

Corresponding author: Dr Ruozhi Xiao, department of Haematology, The Third Department of Haematology, The Third Affiliated Hospital Affiliated Hospital of Sun Yat-sen University, 600 Tianhe of Sun Yat-sen University, Guangzhou, Guangdong Road, Guangzhou 510630, Guangdong Province, China. Province, China Email: [email protected]

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anaemia and multiple petechiae on the Introduction bilateral thighs and buttocks, but without The male sex chromosome superficial lymphadenopathy or hepatosple- 47,XYY is common, with a prevalence nomegaly. His peripheral blood count was ranging between 14.2 and 375 persons per as follows: white blood cell (WBC) count 100000 in newborn boys; it is associated with 0.5 109/l; red blood cell count 2.63 1012/ tall stature, verbal learning disabilities and l; haemoglobin 85 g/l; and platelet count attention deficits.1,2 Behavioural features 17 109/l. The results of a disseminated described in XYY syndrome include intravascular coagulation (DIC) test were increased risk of impulsivity and difficulties as follows: prothrombin time 18.5 s (refer- related to behavioural deregulation.3 In ence value 11–14.5 s); fibrinogen 1.0 g/l (ref- contrast to 47,XXY , erence value 2–4 g/l); active partial boys with XYY syndrome have normal thromboplastin time 40.6 s (reference value pubertal development and 28–40 s); thrombin time 17.1 s (reference levels.4 value 14–21 s); D-dimer >20 mg/ml (refer- Acute promyelocytic leukaemia (APL) is ence value 0–0.5 mg/ml); plasma protamine a speciEc subtype of acute myeloid leukae- paracoagulation test (þ). He had normal mia. The t(15;17)(q22;q21) translocation is testosterone levels and had been married for found in 98% of patients with APL,5 which 5 years but had no offspring. Hepatic and reFects the molecular rearrangement of the renal functions were normal and B ultra- promyelocytic leukaemia (PML) gene. sound showed no abnormality in the liver, Additional chromosomal abnormalities spleen or kidney. His parents and his (ACA) can also be found in patients with brother were healthy. APL in addition to t(15;17)(q22;q21).6,7 The The blast percentage and assessment of prognostic significance of ACA in APL is maturation degree were determined by per- unclear to date, but ACAs can involve any forming a 200-cell leucocyte differential human chromosome. To the best of our count on peripheral blood smears and a knowledge, there have been no previous 500-cell differential count on bone-marrow reports on the coexistence of XYY syn- aspirate smears stained with Wright-Giemsa drome with APL. The present case report stain. Cytochemical tests included myelo- describes a with XYY syndrome diag- peroxidase (POX) reaction, periodic nosed with APL with a PML-RARA inser- acid-Schiff (PAS) reaction and nonspecific tional translocation and chromosome 21 esterase (NSE) reactions. The bone-marrow abnormalities. characteristic showed marked hyperplasia and the granulocytic cell/erythrocytic cell ratio was 40.7. The granulocytic series Case report accounted for 87.5% of the cell population A 29-year-old male was admitted to the with 68.5% of promyelocytes and 14.5% of Department of Haematology, The Third myeloblasts. Promyelocytes were of uneven Affiliated Hospital of Sun Yat-sen cell size with irregular nuclear shapes, University, Guangzhou, Guangdong including being cupped, distorted, folded, Province, China in July 2011 complaining segmented and binucleate. The nucleoli were of repeated fever that had lasted for 2 weeks. obvious and the cytoplasm was filled with His height was 180 cm and weight was 80 kg. pink granules. Cells occasionally had visible He had normal intelligence and did not Auer rods and cytoplasmic projections. The exhibit aggressive behaviour. Physical exam- erythroid lineage showed normal morph- ination showed that he had moderate ology but was severely inhibited by a He et al. 1365

Figure 1. Analysis of a bone-marrow smear from a 29-year-old male who presented with repeated fever that had lasted for 2 weeks revealed the replacement of normal bone-marrow cells by promyelocytic leukaemia cells (Wright-Giemsa stain). The colour version of this figure is available at: http://imr.sagepub.com. Scale bar 10 mm. proportion of 2% in the sample. Lakes, NJ, USA) including antihuman Lymphocytes of normal morphology were cluster of differentiation CD2, CD7, obviously reduced. Megakaryocytes in the CD10, CD19, CD20, CD13, CD33, whole slide could not be found; and platelets CD14, CD34, CD117 and human leucocyte were widely distributed and extremely rare antigen HLA-DR antibodies. Flow cyto- (Figure 1). Cytochemically, the blasts were metric analyses were performed on a BD negative for PAS and NSE and positive for FACSCaliburTM system with BD POX. CellQuestTM software (Becton Dickinson). Bone-marrow samples were cultured for Abnormal cell groups with high-side scat- 24 h and peripheral blood samples were ter that resembled granulocytes were cultured for 72 h at a concentration of 1– observed. Immunophenotypic analysis of 2 106 cells/ml, following standard the blasts demonstrated the following: procedures. R band was performed, and positive for CD13, CD33, and CD117; chromosomes were identiEed and analysed negative for CD34, HLA-DR, CD2, CD7, according to the International System of CD10, CD19, CD20, and CD14. Human Nomenclature (ISCN 2005), which Fluorescence in situ hybridization (FISH) defines the karyotype.8 Cells harvested from was performed to analyse the PML-RARA the bone-marrow sample were dropped onto gene rearrangement involving the four microscope slides. were t(15;17)(q22;q21) and the sex chromosome determined as follows: 47,XYY [14]/ abnormalities. Dual colour-dual fusion 46,XYY,–21[16] and did not show PML/RARA and X/Y centromere probes t(15;17)(q22;q21) (Figure 2). were used (Cytocell, Cambridge, UK). The Bone-marrow aspirate was labelled by a PML/RARA DNA probe hybridizes to panel of directly conjugated monoclonal chromosome 15q22 (spectrum red for the antibodies (Becton Dickinson, Franklin PML gene) and 17q21.1 (spectrum green for 1366 Journal of International Medical Research 42(6)

Figure 2. Karyotype analysis of a bone-marrow sample from a 29-year-old male demonstrated 47,XYY[14]/ 46,XYY,–21[16] chromosomal abnormalities. Aberrant chromosomes are indicated by arrows.

the RARA gene), so the fusion gene is yellow of them had a 2R1G1Y signal pattern, (Y). The is marked in green implying a PML-RARA insertional trans- (G) and the in red (R), so the location (Figure 3A); this was confirmed by normal female has a 0R2G signal pattern FISH analysis (Figure 3B). and the normal male displays a 1R1G signal When the X/Y probe was used, 100% cells pattern. Briefly, the sample of bone marrow had a 2R1G signal pattern, indicating that was dropped onto glass slides and air-dried. cells from the patient had two Y chromo- The slides were immersed in 2 saline somes (Figure 4). In order to rule out sodium citrate (SSC) at 37C for 30 min, whether the additional Y chromosome was then rinsed in a graded series of ethanol associated with leukaemia, karyotypes of (70%, 85% and 100%, each concentration peripheral blood cells were analysed during was applied for 2 min) at room temperature the complete remission period. They were and air-dried. Slides were hybridized for 16 h found to have 47,XYY, which confirmed at 37C in a humidified chamber. After that, that the abnormal Y chromosome was slides were washed in 0.4 SSC/0.3% NP-40 caused by congenital anomalies. for 2 min, then in 2 SSC/0.1% NP-40 for Total cellular RNA was extracted by 30 s. Slides were counterstained with standard laboratory procedures from fresh 0.125 mg/ml 2 -(4-amidinophenyl)-6-indole- bone marrow cells using TRIzolÕ reagent carbamidine dihydrochloride and analysed (Invitrogen, Carlsbad, CA, USA). Reverse under fluorescence microscopy. A total of transcription of the RNA to cDNA was 200 cells were analysed and 90% undertaken using a MaximaTM First Strand He et al. 1367

Figure 3. (A) Fluorescence in situ hybridization (FISH) analysis using a PML/RARA DNA probe on interphase cells. PML gene probe (15q22) was labelled with spectrum red; RARA gene probe (17q21.1) was labelled with spectrum green. One green signal (RARA gene), two red signals (PML gene) and one yellow signal (fusion gene) were noted. Scale bar 10 mm. (B) FISH analysis with the same probe on metaphase cells. The colour version of this figure is available at: http://imr.sagepub.com. Scale bar 10 mm. cDNA Synthesis Kit (Fermentas, Glen indicating that the patient carried the Burnie, MD, USA). Primers for the PML- L-form of the PML-RARA fusion gene, as RARA fusion gene were designed and described in another study on acute leukae- detected as previously described.9 Products mia (Figure 5).9 of the reverse transcription–polymerase After the diagnosis of APL was con- chain reaction (RT–PCR) were separated firmed, the patient was treated with 20 mg on 2% agarose gel and analysed using an all-trans retinoic acid (ATRA), orally, twice ultraviolet transilluminator. Only the daily for 1 week. The patient also received L-form (427 base pairs) of the PML-RARA 2000 AxaIU low molecular weight heparin transcript was amplified by RT–PCR, calcium, twice daily by subcutaneous 1368 Journal of International Medical Research 42(6)

Figure 4. Fluorescence in situ hybridization analysis using X/Y centromere probes. X chromosome is labelled green (G); Y chromosome is labelled red (R). The normal female has a 0R2G signal pattern and the normal male has a 1R1G signal pattern. 2R1G signals were observed, indicating the addition of a Y chromosome. The colour version of this figure is available at: http://imr.sagepub.com. Scale bar 10 mm.

injection for 6 days, and an infusion of fresh regimens were carried out in sequence. In plasma to prevent DIC. The WBC count the first year, these regimens were repeated increased to 12 109/l and blood coagula- four times over the 12-month period. In the tion function returned to normal after treat- second and third years of treatment, the ment for 1 week. Induction chemotherapy three regimens were scheduled to be admin- was carried out as follows: 40 mg darubicin istered in the same sequence, but with a 1- intravenous (i.v.) injection once a day for 3 month treatment-free period between each days; 100 mg cytosine arabinoside i.v. infu- monthly treatment. The chemotherapy regi- sion twice a day for 7 days (known as the mens that were used in the third month DA regimen). The patient achieved com- comprised of either the DA regimen or plete remission after this first course of 10 mg idarubicin i.v. injection once daily chemotherapy. Consolidated treatments for 3 days and 100 mg cytosine arabinoside consisted of three regimens: 10 mg arsenic i.v. infusion twice daily for 7 days (known as trioxide i.v. infusion once daily for 14 days the IDA regimen); or 12 mg mitoxantrone in the first month; 20 mg ATRA adminis- i.v. infusion once daily for 3 days and tered orally twice daily for 28 days in the 100 mg cytosine arabinoside i.v. infusion second month; chemotherapy (see below) in twice daily for 7 days (known as the MA the third month. These three-monthly regimen); or 40 mg pirarubicin i.v. injection He et al. 1369

Figure 5. Detection of the PML-RARA fusion gene transcript by reverse transcription–polymerase chain reaction. Lane M: molecular weight markers (base pairs [bp]); lane S: S-form of PML-RARA transcripts were negative; lane L: L-form (427 bp) of PML-RARA transcripts were amplified; lane N: negative control; lane B: blank control. once daily for 3 days and 100 mg cytosine with Down’s syndrome have an increased arabinoside i.v. infusion twice daily for 7 risk of leukaemia.11 The natural history of days (known as the TA regimen). leukaemia in children with Down’s syn- The patient achieved complete remission drome suggests that 21 and following the first course of treatment and GATA1 genetic contribute to the has received eight courses of chemotherapy, malignant transformation of haematopoi- arsenic trioxide and ATRA during consoli- etic cells.12 Like Down’s syndrome, XYY dated treatment, to date. The patient has syndrome is a chromosomal abnormality survived disease-free for 36 months and has that is often associated with cancer.1 remained in complete remission. After com- A few haematological malignancies have plete remission was achieved, a repeated been reported in patients with XYY syn- cytogenetic analysis of both bone marrow drome, occurring in acute myeloid leukae- and peripheral blood showed the continued mia without maturation, acute myeloid presence of 47,XYY without any evidence of leukaemia with maturation, chronic myeloid the chromosome 21 abnormality, indicating leukaemia, and acute lymphoblastic leukae- that the XYY chromosome aneuploidy was mia.13–17 To the best of our knowledge, this unrelated to the APL. is the first case reporting a patient with 47,XYY syndrome with APL. The male patient described in this current case report Discussion had a tall stature, normal intelligence and Trisomy 21, also known as Down’s syn- testosterone levels, and did not exhibit drome, is associated with an increased inci- aggressive behaviour. Cytogenetic analyses dence of cancer.10 In particular, children of a pretreatment bone-marrow sample, and 1370 Journal of International Medical Research 42(6) postremission samples of bone marrow and gene existed in this patient. These findings peripheral blood, all showed 47,XYY, thus suggest that a combination of conventional XYY syndrome was confirmed. karyotype analysis and molecular methods According to World Health Organization will lead to a more comprehensive under- guidelines,18 the diagnostic criteria for APL standing of genetic changes associated with state that the proportion of abnormal APL and reduce the PML-RARA omission promyelocytes must be >20% by bone- ratio. marrow cell morphological appearance. Chromosomal abnormalities in addition However, if t(15;17)(q22;q21) is observed, to t(15;17)(q22;q21), have been reported in even if the proportion of abnormal promye- between 26% and 39% of APL cases.6,7 locytes is <20%, the patient can still be ACA can involve any human chromosome. diagnosed with APL. In this present case, is the most frequent secondary abnormal promyelocytes accounted for anomaly, although other abnormalities 68.5% of the total cells, although conven- involving chromosomes 1, 3, 7, 9 and 11 tional cytogenetic analysis did not show have been described.6,21 The prognostic t(15;17)(q22;q21). Immunological examin- value of additional cytogenetic changes to ations showed that the abnormal cell group the t(15;17)(q22;q21) remains uncertain. expressed myeloid markers but was negative According to previous reports,22,23 ACA for CD34 and HLA-DR, which accords with constitutes an unfavourable prognosis. the typical appearance of APL. In addition, However, several studies have shown that FISH and RT–PCR analysis demonstrated the coexistence of ACA in patients with the PML-RARA fusion gene. Taking this APL did not affect clinical and biological evidence together resulted in the patient characteristics, complete remission rate, being diagnosed as having APL. disease-free survival rate, overall survival Conventional cytogenetic analysis is the rate or relapse rate.7,21 Wiernik et al.24 main method used to test for reported that treatment with chemotherapy t(15;17)(q22;q21). However, complicated alone did not affect overall survival and translocation variations, including a three- disease-free survival rates of patients with way translocation or the PML-RARA inser- ACA, although when using ATRA treat- tion translocation, also exist; these cannot ment (with or without chemotherapy) be tested by cytogenetic analysis.19,20 These patients who only had t(15;17)(q22;q21) cryptic t(15;17)(q22;q21) rearrangements had higher overall survival and disease-free can be detected by molecular methods, survival rates compared with patients with such as FISH. The use of the dual colour- ACA. These findings suggest that the dual fusion PML/RARA translocation presence of ACA reduced the sensitivity DNA probe with high sensitivity and speci- of cancer cells to the ATRA treatment, ficity detects nearly all of the PML-RARA and reduced the curative effects. The cur- fusion signal of cryptic t(15;17)(q22;q21) rent case had congenital sex chromosome rearrangements. In this current case report, abnormalities followed by chromosome 21 karyotype analysis did not show the loss, but he reached complete remission t(15;17)(q22;q21) rearrangement. However, after the first course of chemotherapy and the interphase FISH analysis showed a has survived disease-free for 36 months. In 2R1G1Y signal pattern, indicating the the current case, ACA involving the sex PML-RARA insertional translocation, chromosomes and chromosome 21 did not which was confirmed by analysis of the appear to affect the outcome of APL, metaphase FISH. RT–PCR analysis con- although the patient had received ATRA firmed that the L-form PML-RARA fusion treatment. He et al. 1371

The specific marker for APL, the effect on leukaemia cells while producing t(15;17)(q22;q21) translocation, has diag- only mild side-effects in the liver and kidney. nostic and prognostic signiEcance. In clin- Chemotherapy was followed by another ical practice, the identiEcation of the course of arsenic trioxide to ensure normal t(15;17)(q22;q21) translocation predicts sen- recovery of haematopoiesis. Meanwhile, sitivity to ATRA.25 The transcription factor arsenic trioxide and ATRA can lessen the PU.1 plays a critical role during myeloid frequency of chemotherapy, which in turn differentiation26 and abnormal activation of reduces bone-marrow injury. As a result of PU.1 is associated with development of the fact that the XYY syndrome involves myeloid leukaemia.27 The PML-RARA pro- multiple organ dysfunction, toxicity from tein can combine with PU.1 to form a PML- chemotherapy can be severe.13,14 However, RARA-PU.1 complex, thus inhibiting PU.1 the case described in this current report expression and the subsequent activation of underwent each course of chemotherapy the target genes controlling the differenti- without experiencing severe side-effects. ation of myeloid progenitor cells; this even- Therefore, the authors recommend that the tually leads to the development of sequential strategy is appropriate for leukaemogenesis.28 However, ATRA can patients with XYY syndrome and APL, as recover PU.1 expression by binding with it was associated with good clinical out- the ATRA receptor domain on the PML- comes and few side-effects. RARA protein, which induces the differen- tiation of leukaemic cells.29 Arsenic binds directly to cysteine residues in zinc fingers Declaration of conflicting interest located within the RBCC domain (which The authors declare that there are no conflicts of includes one RING domain, two B box interest. motifs, and a coiled-coil domain) of the PML-RARA and PML proteins; this induces PML oligomerization, which Funding increases its interaction with the small This research received no specific grant from any ubiquitin-like protein modifier.30 This funding agency in the public, commercial, or not- allows the modified proteins to be degraded for-profit sectors. by proteasome, resulting in the induction of differentiation and apoptosis of the leukae- mia cells.30 Therefore, the complete remis- References sion rate and 5-year disease-free survival 1. Stochholm K, Juul S and Gravholt CH. rate are both above 90% when ATRA is Diagnosis and mortality in 47,XYY persons: a combined with arsenic trioxide to treat registry study. Orphanet J Rare Dis 2010; 5: APL.31 15. In the authors’ institution, APL is treated 2. Sergovich F, Valentine GH, Chen AT, et al. using sequential consolidated regimens that Chromosome aberrations in 2159 consecutive consist of arsenic trioxide followed by newborn babies. N Engl J Med 1969; 280: 851–855. ATRA, and then chemotherapy. These 3. Ross JL, Roeltgen DP, Kushner H, et al. three monthly regimens are carried out in Behavioral and social phenotypes in boys with sequence and repeated over three years, as 47,XYY syndrome or 47,XXY Klinefelter described above, with a 1-month treatment- syndrome. Pediatrics 2012; 129: 769–778. free period between each monthly treatment 4. Aksglaede L, Skakkebaek NE and Juul A. in the second and third years. Using 10 mg/ Abnormal sex chromosome constitution day arsenic trioxide for 14 days had a good and longitudinal growth: serum levels of 1372 Journal of International Medical Research 42(6)

insulin-like growth factor (IGF)-I, IGF 14. Shibata S, Kami M, Kishi Y, et al. Severe binding protein-3, luteinizing hormone, and regimen-related toxicity occurring in a testosterone in 109 males with 47,XXY, patient with XYY syndrome receiving allo- 47,XYY, or sex-determining region of the Y geneic peripheral blood stem cell trans- chromosome (SRY)-positive 46,XX karyo- plantation. Ann Hematol 2002; 81: 407–409. types. J Clin Endocrinol Metab 2008; 93: 15. Sandlund JT, Krance R, Pui CH, et al. XYY 169–176. syndrome in children with acute lympho- 5. Rowley JD, Golomb HM and Dougherty C. blastic . Med Pediatr Oncol 1997; 15/17 translocation, a consistent chromo- 28: 6–8. somal change in acute promyelocytic leu- 16. Midro AT, Wojtukiewicz M, Bielawiec M, kaemia. Lancet 1977; 1: 549–550. et al. XYY syndrome and acute myeloblastic 6. Cervera J, Montesinos P, Herna´ ndez-Rivas leukemia. Cancer Genet Cytogenet 1987; 24: JM, et al. Additional chromosome abnorm- 363–365. alities in patients with acute promyelocytic 17. Atichartakarn V, Punyammalee B, leukemia treated with all-trans retinoic acid Wongsasant B, et al. Acute nonlymphocytic and chemotherapy. Haematologica 2010; 95: leukemia with a translocation (1;3)(p36;q21) 424–431. in an XYY man. Cancer Genet Cytogenet 7. Ono T, Takeshita A, Iwanaga M, et al. 1986; 21: 79–83. Impact of additional chromosomal 18. Vardiman JW, Harris NL and Brunning RD. abnormalities in patients with acute pro- The World Health Organization (WHO) myelocytic leukemia: 10-year results of classification of the myeloid neoplasms. the Japan Adult Leukemia Study Group Blood 2002; 100: 2292–2302. APL97 study. Haematologica 2011; 96: 19. Grimwade D, Biondi A, Mozziconacci MJ, 174–176. et al. Characterization of acute promyelocy- 8. Shaffer LG, Tommerup N (eds) ISCN 2005: leukemia cases lacking the classic t(15;17): An international system for human cytogen- results of the European Working Party. etic nomenclature. Basel, Switzerland: Groupe Franc¸ ais de Cytoge´ ne´ tique S. Karger, 2005. He´ matologique, Groupe de Franc¸ ais 9. Pallisgaard N, Hokland P, Riishøj DC, et al. d’Hematologie Cellulaire, UK Cancer Multiplex reverse transcription-polymerase Group and BIOMED 1 chain reaction for simultaneous screening of European Community-Concerted Action 29 translocations and chromosomal aberra- ‘‘Molecular Cytogenetic Diagnosis in tions in acute leukemia. Blood 1998; 92: Haematological Malignancies’’. Blood 2000; 574–588. 96: 1297–1308. 10. Ayed W, Gouas L, Penault-Llorca F, et al. 20. Wan TS, So CC, Hui KC, et al. Diagnostic Trisomy 21 and cancers. Morphologie 2012; utility of dual fusion PML/RARalpha 96: 57–66 [in French, English abstract]. translocation DNA probe (D-FISH) in acute 11. Buitenkamp TD, Izraeli S, Zimmermann M, promyelocytic leukemia. Oncol Rep 2007; 17: et al. Acute lymphoblastic leukemia in chil- 799–805. dren with : a retrospective 21. Herna´ ndez JM, Martı´ n G, Gutie´ rrez NC, analysis from the Ponte di Legno study et al. Additional cytogenetic changes do not group. Blood 2014; 123: 70–77. influence the outcome of patients with newly 12. Khan I, Malinge S and Crispino J. Myeloid diagnosed acute promyelocytic leukemia leukemia in Down syndrome. Crit Rev treated with an ATRA plus anthracyclin Oncog 2011; 16: 25–36. based protocol. A report of the Spanish 13. Sada E, Henzan H, Ohtani R, et al. group PETHEMA. Haematologica 2001; 86: Conditioning with targeted busulfan for 807–813. autologous peripheral blood stem cells 22. Schlenk RF, Germing U, Hartmann F, et al. transplantation for acute myelogenous leu- High-dose cytarabine and mitoxantrone in kemia in an XYY male. Am J Hematol 2005; consolidation therapy for acute promyelo- 78: 55–58. cytic leukemia. Leukemia 2005; 19: 978–983. He et al. 1373

23. Bastos EF, Silva LA, Ramos MC, et al. 27. Tenen DG. Disruption of differentiation in Trisomy 11 as an additional chromosome human cancer: AML shows the way. Nat Rev alteration in a child with acute promyelocytic Cancer 2003; 3: 89–101. leukemia with poor prognosis. Case Rep 28. Wang K, Wang P, Shi J, et al. PML/ Genet 2012; 2012: 659016. RARalpha targets promoter regions con- 24. Wiernik PH, Sun Z, Gundacker H, et al. taining PU.1 consensus and RARE half sites Prognostic implications of additional in acute promyelocytic leukemia. Cancer Cell chromosome abnormalities among patients 2010; 17: 186–197. with de novo acute promyelocytic leukemia 29. Mueller BU, Pabst T, Fos J, et al. ATRA with t(15;17). Med Oncol 2012; 29: resolves the differentiation block in t(15;17) 2095–2101. acute myeloid leukemia by restoring PU.1 25. Fang J, Chen SJ, Tong JH, et al. Treatment expression. Blood 2006; 107: 3330–3338. of acute promyelocytic leukemia with ATRA 30. Zhang XW, Yan XJ, Zhou ZR, et al. Arsenic and As2O3: a model of molecular target- trioxide controls the fate of the PML- based cancer therapy. Cancer Biol Ther 2002; RARalpha oncoprotein by directly binding 1: 614–620. PML. 2010; 328: 240–243. 26. Rosenbauer F and Tenen DG. Transcription 31. Wang ZY and Chen Z. Acute promyelocytic factors in myeloid development: balancing leukemia: from highly fatal to highly curable. differentiation with transformation. Nat Rev Blood 2008; 111: 2505–2515. Immunol 2007; 7: 105–117.