Leukemia (1999) 13, 1534–1538  1999 Stockton Press All rights reserved 0887-6924/99 $15.00 http://www.stockton-press.co.uk/leu Identification of novel chromosomal rearrangements in acute myelogenous leukemia involving loci on chromosome 2p23, 15q22 and 17q21 A Melnick1, S Fruchtman1, A Zelent2, M Liu3, Q Huang3, B Boczkowska1, MJ Calasanz4, A Fernandez4, JD Licht5 and V Najfeld1

1Division of Hematology, Tumor Cytogenetics Laboratory, and 5Derald H Ruttenberg Cancer Center, Mount Sinai Medical Center, New York, NY, USA; 2Institute of Cancer Research London, UK; 4University of Navarra and Hospital San Milagros, Spain; and 3Shanghai Institute of Hematology, China

Chromosomal translocations are frequently linked to multiple Case reports hematological malignancies. The study of the resulting abnor- mal gene products has led to fundamental advances in the understanding of cancer biology. This is the first report of Patient 1 t(2;15)(p23;q22) and t(2;17)(p23;q21) translocations in human malignancy. Patient 1, a 73-year-old male, was diagnosed with A previously healthy 73-year-old male, presented in June myeloblastic (FAB M1 sub-type) AML. Cytogenetic analysis showed a 47,XY,t(2;15)(p23;q22),+13 karyotype. Fluorescent in 1996 with acute myeloblastic leukemia (FAB M1 sub-type). situ hybridization (FISH) showed that the PML gene was trans- The patient was treated with standard induction chemo- ferred intact to the short arm of chromosome 2 while the ALK therapy consisting of cytosine arabinoside and idarubicin and gene on chromosome 2p23 was passively transferred to the achieved complete remission. He subsequently underwent long arm of chromosome 15. Patient 2 was a 60-year-old male one cycle of consolidation chemotherapy with cytosine arabi- diagnosed with monocytic (FAB M4-type) AML. Cytogenetic noside and remained in complete remission. In December of analysis showed 46,XY,t(2;17)(p23;q21) karyotype. FISH analy- sis showed that neither RAR␣ nor ALK were disrupted by the 1996 he was noted to be leukopenic with blasts noted in the translocation. None of the coding region of the three genes peripheral smear. Relapse of AML was diagnosed and a studied were translocated in these patients. This raises the second course of identical induction chemotherapy was possibilities that other neighboring genes could be involved or administered but this time without response. A bone marrow that noncoding regulatory sequences of the studied genes biopsy and aspirate revealed a hypercellular bone marrow could be put in contact and deregulate expression of other with 20% myeloblasts – consistent with the RAEB (refractory genes. Alternatively, displacement of ALK, RAR␣ and PML to novel positions could lead to loss of their normal regulation anemia with excess blasts) variety of myelodysplasia. Cyto- Keywords: translocation; acute myelogenous leukemia; fluor- genetic analysis in all 30 metaphases studied showed a escent in situ hybridization; cytogenetics; tumor genetics 47,XY,t(2;15)(p23;q22),+13 karyotype. The patient sub- sequently had a rapid increase in his leukocyte count and replacement of the bone marrow with a monomorphic Introduction infiltrate of blasts, and died shortly thereafter.

Consistent chromosomal translocations associated with spe- cific subtypes of acute leukemia have both diagnostic and Patient 2 prognostic significance. For example, the t(8;21) which fuses the genes ETO/MTG8 and AML-1/CBF␣ is both diagnostic for 1–3 A 60-year-old male presented in December 1996 with fatigue, M2 AML and is a marker for favorable prognosis. Another weight loss, dyspnea and hemoptysis for several weeks. There example is the translocation disrupting the retinoic acid recep- was an acute loss of strength of the right upper and lower tor ␣ gene – which is diagnostic for acute promyelocytic leu- extremities. The patient had a previous history of bladder kemia (APL) when fused to loci 15q22, 11q23, 5q35 and 4 polyps, chronic pulmonary disease as well as heavy smoking 11q13. These regions encode the genes for PML and alcohol use. He had thrombocytopenia, macrocytic ane- (promyelocytic leukemia), PLZF (promyelocytic leukemia zinc mia and generalized lymphadenopathy as well as a granulo- finger), NPM (nucleophosmin) and NuMA (nuclear matrix- cyte count of 150 000/␮l. A bone marrow study revealed a mitosis associated). APL associated with t(15;17) is uniquely hypercellular marrow with 70% blasts. Morphologic and sensitive to treatment with retinoic acid, however, the cytochemical analysis was consistent with monoblastic (FAB t(11;17)(q21;q23) translocation predicts for disease that is M4-type) AML. Cytogenetic analysis showed a resistant to this modality. These loci have been uniquely asso- 46,XY,t(2;17)(p23;q21) karyotype. The patient was then ciated with APL and have not been described in any other treated with standard induction chemotherapy consisting of form of leukemia. We describe two clinical cases of leukemia cytosine arabinoside and idarubicin, however, there was no with novel chromosomal rearrangements involving 15q22 and response to treatment and he died shortly after. 17q21 and which did not have the phenotype of APL. Interest- ingly, both of these loci were re-located to the short arm of chromosome 2. This area contains the ALK (anaplastic lym- phoma kinase) gene – which is involved in anaplastic large Materials and methods cell lymphoma associated with a translocation between chromosomes 2 and 5. Cytogenetics

Correspondence: A Melnick, Box 1079, Mount Sinai Medical Center, Chromosomes were obtained from bone marrow cells using 5 New York, NY, 10029, USA; Fax: (212) 987-8566 previously described methods. ISCN (1995) nomenclature Received 2 December 1998; accepted 25 May 1999 was used to describe the karyotypes.6 Novel chromosomal rearrangements in AML A Melnick et al 1535 Fluorescence in situ hybridization (FISH) unaffected by the translocation. Figure 2 shows translocation 2;17 from patient 2 and relocation of both the 3Ј and 5Ј por- An aliquot of cytogenetic cell suspension was used for FISH tion of the intact RAR␣ gene to chromosome 2. The fact that studies. Slides were denatured at 75°C for 5 min in 60% both probes co-localize on chromosome 2 rules out any poss- formimide/2 × SSC and hybridized overnight with a dual color ible internal breakpoints in the coding regions of RAR␣.If PML-RAR␣ probe (Vysis, Downers Grove, IL, USA) as well as such a breakpoint did occur, there would be separation of the with two ALK probes (obtained as gifts from Dr Steve Morris red and green hybridization signals on chromosome 2. FISH and from Vysis). Post-hybridization washings were according studies with dual color PML (red)/RAR␣ (green) revealed the to the manufacturer’s instructions. Two hundred ng of ALK normal localization of PML on chromosome 15q22. probe was used for hybridization and post-hybridization washings were the same as for PML-RAR␣. Metaphase chro- mosomes were counterstained with 4Ј,6-diamidino-2-phe- Discussion nylindole (DAPI). In addition to the above, for patient 1, a probe for the PML 3Ј non-coding sequences were used We identified two novel translocations, t(2;15)(p23;q22) and (obtained as a gift from Vysis). For patient, 2 RAR␣ 3Ј and 5Ј t(2;17)(p23;q21) in the setting of acute myelogenous leuke- probes labeled in different colors were used (Vysis). Images of mia. The breakpoints involved in these rearrangements are chromosomes for both patients were taken using Zeiss micro- localized to the 2p23, 15q22 and 17q21 loci. These translo- scope connected to a Cytovision System (Applied Imaging, cations involve regions which are known to be rearranged in Pittsburgh, PA, USA). other hematologic malignancies but never in this pattern. Indeed, to our knowledge, this is the first report of these trans- locations in any hematologic malignancy. Results The 17q21 locus is the site of a number of gene products. Prominent among these is the RAR␣ gene product.7 RAR␣ is All 30 evaluated metaphases from patient 1 showed rearranged as a fusion product in acute promyelocytic leuke- rearrangements between the short arm of chromosome 2 and mia4 most commonly with the PML gene which is located on long arm of chromosome 15 as well as trisomy 13. The kary- chromosome 15q22. RAR␣ is upregulated during commitment otype was 47,XY,t(2;15)(p23;q22),+13. All 50 evaluated meta- to the myeloid lineage and may regulate the expression of a phases from patient 2 showed rearrangements between the large host of genes critical to the myeloid phenotype.4 Such short arm of chromosome 2 and the long arm of 17. The kary- targets include neutrophil granule proteins, cell surface otype was 46,XY,t(2;17)(p23;q21). The nature of these translo- adhesion molecules, colony-stimulating factors, colony-stimu- cations, involving loci usually associated with APL, led us to lating factor receptors, cytokines, etc.4 Understanding the perform gene mapping to further evaluate the origin of these biology and mechanism of action of RAR␣ fusion proteins rearrangements. Metaphase FISH studies were performed to resulted in highly successful novel therapeutic approaches detect possible disruptions of PML, RAR␣ and ALK. which directly target the molecular mechanisms of leuke- Figure 1 shows translocation (2;15) from patient 1 and relo- mogenesis in acute promyelocytic leukemia.4 cation of intact PML to the short arms of chromosome 2. To determine whether the RAR␣ gene was involved in Additional FISH studies demonstrated a reciprocal translo- patient 2, we performed FISH assays, which demonstrated that cation of intact ALK from 2p23 to the deleted chromosome 15 using the 3Ј PML probe. In this case, the RAR␣ gene was

Figure 2 A partial karyotype from patient 2 showing t(2;17). RARA (green) from chromosome 17 was translocated to chromosome 2 after FISH studies utilizing dual color PML-RARA probes (left panel from Figure 1 A partial karyotype from patient 1. Metaphase FISH study the idiogram). The right panel shows der(2)t(2;17) and normal chro- with PML-RARA (left panel from idiogram) showing a translocation of mosome 17 after metaphase FISH utilizing dual color 5ЈRARA PML (red signal) from 15q22 to 2p23. Note a normal distribution of (red)/3ЈRARA (green). Any breakpoint in RARA gene will cause the RARA on 17q21. The right panel shows chromosomes 2 and 15 after separation of green and red hybridization signal. The observation that dual color FISH studies with ALK (green) and 3ЈPML (red). Note the green and red signals are fused resulting in a yellow hybridization translocation of ALK from 2p23 to del(15) and intact translocation of signal strongly suggests that RARA gene was intact when translocated 3Ј PML from 15q22 to chromosome 2. to chromosome 2. Novel chromosomal rearrangements in AML A Melnick et al 1536 RAR␣ was not disrupted. In light of the fact that RAR␣ disrup- Several other genes interesting from the leukemia point of tion appears to be responsible for the promyelocytic pheno- view are also present on 15q22. Prominent among these is type of APL cells8 this is not a surprising finding. Indeed, the MEK1 gene.30 MEK1 forms part of the MAP kinase signal expression of dominant negative forms of RAR␣ in hematopo- transduction cascade, can induce cellular transformation when ietic cells, or the even the forced overexpression of wild-type mutated and is functionally linked to the cell cycle.31–33 To RAR␣, result in differentiation block at the promyelocyte stage date, MEK1 has not been found to be rearranged or mutated of development. This may be due to sequestration of RAR␣ in AML. Also located at 15q22 is the Tle-3 gene, a member partner protein RXR, thus inhibiting proper interaction of these of the notch signaling pathway.34 Mutations of notch pathway proteins with their target promoters.4 Consistent with the members (although not Tle-3) have been demonstrated in T observed non-involvement of RAR␣, this patient had a non- cell acute lymphoblastic leukemia.35 Another notch pathway APL phenotype and was classified as M4 AML. gene, the metalloprotease-disintegrin kuz, also localizes to However, it is possible that the disruption of 17q21 resulted this locus.36 Kuz is overexpressed in certain neoplasias and is in the disturbance of other genes. Several other gene products involved in cleaving notch ligand precursors located on the from this area are linked to human malignancies. One of these cell surface.36,37 Finally, the ERC-55 gene codes an endo- is the familial breast–ovarian cancer BRCA1 gene,9 a tumor plasmic reticulum-associated protein which binds to the suppressor which may be involved in DNA repair and tran- papillomavirus E6 oncoprotein.38,39 scriptional regulation.10,11 A number of other genes critical for Both of our patients harbored rearrangements affecting the cellular differentiation and growth are located at 17q21.12 2p23 locus. This band region is a well known target for disrup- These include: tion in different leukemias. Previously reported translocations involving this locus include: • The HOXB cluster of homeotic proteins,12 several of which are involved in hematopoietic cell differentiation.13 In • t(2;4)(p23;q25), t(2;4)(p23;q31), t(2;4)(p23;q35) and addition, murine models show that forced overexpression t(2;3)(p23;q26) in M2 acute myelogenous leukemia.40–43 of certain HOXB genes can lead to proliferation of hemato- • t(2;5)(p23;q35) in the setting of chromic eosinophilic leuke- poietic progenitor cells and, in the case of HOXB8, to late mia.44 onset AML.13 • Deletion(2)(p23) either as solitary or complex abnormalities • The chromatin remodeling and transcriptional machinery in primary and secondary AML.45–47 adapter proteins GCN5L2 and TADA2L.14,15 Recent reports Thus, disruption of chromosome 2 at the p23 locus appears have demonstrated that deregulation of proteins such as to be a recurring genetic lesion in leukemias. This suggests transcriptional co-activators, co-repressors, histone acetyl- that one or more as yet undetermined 2p23 genes, when alt- ases and histone deacetylases, is an important mechanism ered by translocation, can disregulate growth control and dif- in several types of leukemia. For example, the interaction ferentiation of myeloid progenitor cells. of chimeric proteins resulting from translocations found in One of the prominent genes at 2p23 is named ALK,48 a APL and t(8;21) M2 AML with these chromatin remodeling membrane spanning protein tyrosine kinase with homology to mediators may be central to their pathogenic role4,16,17 and LTK (64%), TRKA (38%), ROS (37%), Sevenless (35%), ␤IGF- indicates a common pathway of leukemogenesis. 1(37%) and ␤IR (36%). It forms a chimeric fusion product with • The E1A-F transcription factor gene, which induces proteins the nucleophosmin gene on chromosome 5q35 in the subset involved in invasion and metastasis such as matrix metallo- of patients with anaplastic large cell lymphoma that harbor the proteinases, and is upregulated in invasive cancer.18–23 E1A- t(2;5)(p23;q35) translocation.48 We analyzed leukemic cells of F is targeted for translocation in the certain cases of child- both patients using FISH to determine whether ALK was dis- hood sarcomas.24,25 rupted. In neither case was there any evidence of ALK • The cdc6 cell cycle regulatory protein26,27 which has a key rearrangements. FRA-2,49 a fos transcription factor family role in DNA replication during S phase. member, is also localized to this region. Interestingly, fos tran- • Numerous others, including hox-like genes, other transcrip- scription factors may participate in the differentiation of early tion factors and signaling transduction pathway mediators.12 hemopoietic cells50 and may predispose leukemic cells It is interesting to speculate whether any of these genes – towards differentiation. Thus, it is tempting to speculate that many of which may be involved in mechanisms governing the disruption of a fos gene such as FRA-2 could contribute cellular differentiation, cycling and growth – could be partly to the leukemogenic process, either by inactivating the gene responsible for the leukemic properties of this patient’s cells. via a dominant negative effect or via an aberrant oncogenic The PML (promyelocytic leukemia) gene localized on chro- gain of function. mosome 15q22 is the fusion partner of RAR␣ in more than Finally, in addition to abnormalities caused by internal dis- 90% of APL patients.4 PML localizes to specific subnuclear ruptions of gene loci, positional effects caused by displace- structures know as nuclear bodies which are disrupted in APL ment of regulatory elements to the proximity of heterotopic and in viral infections.4 Multiple functions have been assigned genes can result in inappropriate expression patterns of pro- to PML, such as roles in apoptosis, growth suppression, teins, contributing to the transformed state. For example, dis- immune response pathways as well as the transcriptional and placement of the BCL6 transcription factor to the IGH post-transcriptional regulation of gene expression.4,28,29 Fur- (immunoglobulin heavy chain locus) results in a loss of the thermore, observations in PML null mice strongly suggest a normal down-regulation of this protein as B cells exit the ger- tumor suppressor function for PML. For example, these ani- minal center, contributing to the development of diffuse large mals had double the incidence of lymphomas when treated cell lymphoma.51 Multiple different translocations fusing the systemically with the chemical tumor initiator DMBA as com- IGH or T cell receptor (TCR) regulatory region loci to pared to control mice.29 FISH performed on the leukemic cells mediators of cell survival or proliferation result in B cell and from patient 1 revealed that the PML locus was intact in this T cell neoplasms.51 In the same fashion, the normal pattern patient. Therefore it is highly probable that a different gene of expression of the gene products discussed above may be product is targeted in the 15q22 regions. altered by the disruption of surrounding upstream or down- Novel chromosomal rearrangements in AML A Melnick et al 1537 stream regulatory elements. This might result in ectopic human transcriptional adaptor genes TADA2L and GCN5L2 colo- expression, overexpression or suppression of one or more of calize to chromosome 17q12-q21 and display a similar tissue these proteins. expression pattern. Genomics 1997; 40: 497–500. 15 Struhl K, Moqtaderi Z. The TAFs in the HAT. Cell 1998; 94: 1–4. In conclusion, we have described two novel translocations 16 Kitabayashi I, Yokoyama A, Shimizu K, Ohki M. Interaction and in acute myelogenous leukemia. These translocations functional cooperation of the leukemia-associated factors AML1 involved breakage near loci known to be involved in hemato- and p300 in myeloid cell differentiation. EMBO J 1998; 17: logical malignancies and which may have pathophysiologic 2994–3004. significance. However, none of these genes were disrupted, 17 Lutterbach B, Westendorf JJ, Linggi B, Patten A, Moniwa M, Davie suggesting that there are other genes in these chromosomal JR, Huynh KD, Bardwell VJ, Lavinsky RM, Rosenfeld MG, Galss C, Seto E, Hiebert SW. ETO, a target of t(8;21) in acute leukemia, regions whose translocation could contribute to the transform- interacts with the N-CoR and mSin3 corepressors. Mol Cell Biol ation of hemopoietic cells into leukemic blasts. Several inter- 1998; 18: 7176–7184. esting candidates have been mentioned although there is no 18 Isobe M, Yamagishi F, Yoshida K, Higashino F, Fujinaga K. Assign- evidence that these gene products are altered in these patients. ment of the ets-related transcription factor E1A-F gene (ETV4) to Further investigations of the gene rearrangements at the 2p23, human chromosome region 17q21. Genomics 1995; 28: 357– 15q22 and 17q21 loci will undoubtedly yield a greater under- 359. standing of the molecular pathogenesis of AML. 19 Higashino F, Yoshida K, Noumi T, Seiki M, Fujinaga K. Ets-related protein E1A-F can activate three different matrix metalloproteinase gene promoters. Oncogene 1995; 10: 1461–1463. 20 Hida K, Shindoh M, Yoshida K, Kudoh A, Furaoka K, Kohgo T, Acknowledgements Fujinaga K, Totsuka Y. Expression of E1AF, an ets-family transcrip- tion factor, is correlated with the invasive phenotype of oral squamous cell carcinoma. Oral Oncol 1997; 33: 426–430. We would like to thank Dr Steve Morris (Department of Hem- 21 Hida K, Shindoh M, Yasuda M, Hanzawa M, Funaoka K, Kohgo atology-Oncology, St Jude Children’s Research Hospital, T, Amemiya A, Totsuka Y, Yoshida K, Fujinaga K. Antisense E1AF Memphis, TN) for his generous gift of the ALK probe used in transfection restrains oral cancer invasion by reducing matrix met- our FISH experiments, as well as the Vysis Corporation for alloproteinase activities. Am J Pathol 1997; 150: 2125–2132. their generous gift of the other ALK probe described in this 22 Taguchi K, Yoshida K, Sasaki F, Fujinaga K. Two transcription fac- publication. AM is supported by NCl KO8 CA73762–01. JDL tors, E1AF and N-myc, correlate with the invasiveness of neuro- is supported by NIH R01 CA59936. JDL is a scholar of the blastoma cell lines. Jpn J Cancer Res 1997; 88: 394–400. 23 Shindoh M, Higashino F, Kaya M, Yasuda M, Funaoka K, Han- Leukemia Society of America. zawa M, Hida K, Kohgo T, Amemiya A, Yoshida K, Fujinaga K. Correlated expression of matrix metalloproteinases and ets family transcription factor E1A-F in invasive oral squamous-cell-carci- References noma-derived cell lines. 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