Variant Complex Translocations Involving Chromosomes 1, 9, 9, 15

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Variant complex translocations involving chromosomes 1, 9, 9, 15 and 17 in acute promyelocytic leukemia without RAR␣/PML gene fusion rearrangement SK Gogineni1, HO Shah2, M Chester2, JH Lin2, M Garrison2, A Alidina2, E Bayani2 and RS Verma1

1Division of Genetics, The Long Island College Hospital-SUNY, Health Science Center at Brooklyn, NY, and 2Department of Pathology, Nassau County Medical Center, East Meadow, NY, USA

Acute promyelocytic leukemia (APL;M3) is specifically charac- Case report terized by a predominance of malignant promyelocytes having atypical reciprocal translocation involving chromosome 15 and 17 [t(15;17)(q22;q11)] resulting in the fusion of retinoic acid A 35-year-old Hispanic woman was admitted to the hospital receptor alpha (RAR␣) on chromosome 17 and the putative with low WBC count. Hematological data of the patient are transcription factor gene PML, ie the translocation generates × 12 ␣ ␣ as follows: RBC 2.56 10 /l, Hb 9.69 g/dl, Hct 24.7%, MCV two fusion transcripts, PML/RAR and RAR /PML. We describe × 3 ␮ × 9 a patient with clinical and morphologic characteristics of atypi- 96 Fl, platelets 49 10 / l, WBC 0.9 10 /l with 22.4% neu- cal APL but with a previously undescribed variant translo- trophils, 32% monocytes, 0.5% eosinophils, 0.2% basophils cation. A 35-year-old Hispanic having atypical APL was referred and rare myeloblasts. The bone marrow findings were consist- for cytogenetic evaluation. The cytogenetic findings with GTG- ent with acute myeloid leukemia (AML-M3) or APL. She was banding coupled with FISH analysis revealed the following kar- treated with all-trans retinoic acid (ATRA) and at that time the yotype: 46,XX,der(9)t(1;9)(q25;q34)der(9)t(9;?)(q34;?), t(15;17)- ؉ ؉ fibrinogen and D-dimer were 121 mg/dl and less than (q22;q11)ish. der(9)t(1;9)(q25;q34)(WCP1 ,WCP9 ),t(9;17;15)- ␮ ,q34;q11;q22) (WCP9؉,WCP15؉,PML؉;WCP17؉,RAR␣؉;- 1.0 g/ml, respectively. Two weeks following treatment) WCP15؉,WCP17؉,PML−)[20]/46,XX[5]. The chromsome 17q fibrinogen was increased to 471 mg/dl and the WBC count was translocated to the chromosome 15q. However, chromo- decreased to 3.8 × 103/ml from 34.5 × 103/ml. The patient had some 15q including the PML gene normally translocating to 17q several days of bone pain in the sternum and shoulder as the and creating the RAR␣/PML fusion gene, translocated to chro- leukocyte count rose. Chest X-ray showed small right pleural mosome 9q. Does this patient have another subset of APL? Or effusion and infiltrate which improved immediately following is the genetics of APL different in cases with variant translocations as opposed to those with atypical t(15;17) translo- administration of ceftazimide. The patient expired. cation, though in the majority of the cases their clinical presen- tation remains the same. Keywords: acute promyelocytic leukemia; RAR␣ and PML gene; chromosomes 15 and 17; variant translocations Materials and methods

Introduction Cytogenetic analysis was performed from bone marrow speci- mens using a routine protocol.45 Fluorescence in situ hybridiz- Acute promyelocytic leukemia (APL) has been characterized ation (FISH) was carrried out employing whole chromosome by atypical morphology (FAB M3) having a balanced translo- painting probes (WCP) for chromosome 1, 9, 15 and 17 cation between the long arms of chromosomes 15 and 17, (GIBCO/BRL, Gaithersburg, MD, USA), and the APL t(15;17) t(15;17)(q22q21). In 95% of cases it has been a hallmark cyto- translocation probe (Oncor, Gaithersburg, MD, USA) that 1,2 specifically identifies the regions of the PML (green) and RAR␣ genetic marker since 1976. In recent years, a number of ␣ investigators have unveiled the molecular biology underlying (red) genes involved in the RAR /PML gene fusion. All pro- the t(15;17) of APL.3–7 The genes which are involved in this cedures were as recommended by the manufacturer. Briefly, slides were air dried for at least 2 days prior to denaturation, translocation are PML on chromosome 15 and the locus that × ° encodes for retinoic acid receptor alpha (RAR␣) on chromo- then denatured in 70% formamide/2 SSC at 70 C for 10– 8 15 s each and passed through an ethanol dehydration series. some 17 have been isolated and cloned. Fusion genes are ° formed and their abnormal products are PML/RAR␣ and WCP probes were denatured for 10 min at 70 C prior to RAR␣/PML fusion protein resulting in promyelocytic leuke- hybridization while the loci-specific translocation probe was 9–16 hybridized without denaturation. All probes were hybridized mogenesis. Henceforth, this cytogenetic entity has become ° a routine diagnostic parameter where both genes can be vis- at 37 C in a moist chamber overnight. The stringency of the ualized by fluorescent in situ hybridization.17 Though t(15,17) post-hybridization washes were: for the loci-specific probes 18,19 1 × SSPE at 70°C for 5 min and for the WCP probes 50% has been a distinctive translocation, a number of variant × × ° translocations have been observed in APL.20–44 In a few cases, formamide/2 SSC (pH 7.0), 2 SSC/0.1% NP-40 at 45 C. it has been suggested that the breakpoint on 17q rather than WCP probes were spectrum orange or spectrum green flu- on 15q is the clinical region in atypical APL, while others have orophore-labeled and the hybridization included unlabeled competitor human Cot-1 DNA. The translocation loci specific disagreed. We report an atypical case of APL with previously ␣ undescribed unusual cytogenetic findings but without an probe was rhodamine-labeled (RAR ) and fluorescein-labeled apparent fusion of the RAR␣/PML gene. (PML) and detected with rhodamine-labeled anti-digoxigenin and fluorescein-labeled anti-avidin. DAPI/phenylenediamine dihydrochloride was used as a counter stain. The images were captured on an Oncor Imaging system with a three chip Correspondence: RS Verma, Division of Genetics, The Long Island cooled camera. Another sample for Southern blotting and College Hospital, 339 Hicks Street, Brooklyn, NY 11201-5514, USA reverse transcriptase-polymerase chain reaction (RT-PCR) Received 26 September 1996; accepted 16 December 1996 could not be obtained as the patient expired. APL without RAR␣/PML gene rearrangement SK Gogineni et al 515 Table 1 Variant translocations in acute promyelocytic leukemiaa

Case No. Abnormalities Refs

1 t(1;5;15;17)(p36;q31;q22;q12) Ohyashiki et al30 2 t(1:15;17)(q23;q22;q23) Galieni et al62 3 t(1;15;17)(p36;q22;q21.1) Osella et al23 4 t(1,3,17)(p22;p25;q21) Park et al29 5 t(2;15;17)(q2?;q25 or q26;q21 or 22) Bernstein et al31 6 t(2;15;17)(q21;q21;q22;q2u) Bjerrum et al32 7 t(3;15;17)(p21;q25 or 26;q21 or 22) Bernstein et al33 8 t(3;17;15)(p21;q21;q22) Berger et al34 9 t(4;15;17)(q21;q22;q12) McKinney et al25 10 t(5;15;16;17)(q22;q22;p13;q12) Zaccaria et al63 11 t(8;15;17)(p12;q22;q21) Miura et al64 12 t(11;15;17)(q11;q15;q21) Casula et al66 13 t(13;15;17;20)(q22;q22;q12;q13) Zaccaria et al63 14 t(X;15;17)(q13;q21;q21) Callan et al35 15 t(15;17;18)(q21;q12;q12) Ogawa et al24 16 t(15;?18;17)(q22;?q22;q22) Grimwade et al59 17 t(15;16;17;19)(q22;q13;q12;p13.3) Kamal et al71

18 t(1;17)(p?q21;22) Yamada et al36 19 t(1;17)(p36;q21) Schwartz et al37 20 t(5;17)(q32;q12) Corey et al65 21 t(7;17)(q36;q22) Yamada et al36 22 t(8;17)(p12 or 21;q12) Sonoda et al38 23 t(11;17)(q25;q21) Schwartz et al37 24 t(11;17)(q13;q12) Najfeld et al39 25 t(11;17)(q22–23) Chen et al40 26 t(11;17)(q23;q21) Licht et al47 27 t(11;17)(q23.24;q12.21) Guidez et al67

28 del(17)(q22) van den Berghe et al41 29 del(17)(q11q21 or 22) Barletta et al42 30 del(17)(q22 or 24) Knuutila et al43

31 i(17q) Baranger et al68

32 del(15)(q22q26) Zahavi et al44 33 t(3;15)(q21;q22) Heim et al21 34 t(X;15)(q11;q22) Srivastava et al22

35 t(15;17)(q22;q21)/t(6;17)(p24;q21)/t(15;17)(q22;q21) Arranz et al28 36 der(1)(q44),der(6)(q12);der(7)(q36);t(15;17)(q21;q21) Kizaki et al49 37 t(1;9)(q25;q34),t(9;17;15)(q34;q11;q22) Present case aThere are several dozen variant as well as normal cases where chromosomes 15 and 17 are not apparently involved cytogenetically in translocations.52

Results and discussion were concluded as follows: 46,XX,der(9)t(1;9)(q25;q34)der(9) t(9;?)(q34;?), t(15;17)(q22;q11)ish. der(9)t(1;9) (q25;q34) Initial cytogenetic evaluation of a 24-h unstimulated bone (WCP1+,WCP9+), t(9;17;15)(q34;q11;q22)(WCP9+,WCP15+, marrow cell culture revealed metaphases with abnormal chro- PML+;WCP17+, RAR␣+;WCP15+, WCP17+,PML−) [20]/46, mosomes 1, 9, 9, 15 and 17 whose morbidity could not be XX[5]. Briefly, one chromosome 9 had an additional 1q trans- revealed by G-banding alone. Later, by FISH technique using located to 9q34. There was a three way translocation involv- whole chromosome paint and the t(15;17) translocation-spe- ing the other chromosome 9 and chromosomes 17 and 15 cific probe, the complex chromosome abnormalities were where the distal portion of 17q at RAR␣ translocated to its unmasked as t(1;9)(q25;q34);t(9;17;15)(q34;q11;q22). APL usual location on chromosome 15. The distal 15 at PML trans- t(15;17) loci specific probe was hybridized to the metaphases located to chromosome 9q34 and the distal 9q34 translocated to determine if the fusion of RAR␣/PML gene on chromosomes to chromosome 17q (Figure 1). Srivastava et al22 reported an 15 and 17 had occurred. Although 17q was translocated to atypical case of APL with a t(X;15)(q11;q22) in which chromo- 15q confirmed by WCP 17 and implying the presence of the some 17 was not apparently involved in the translocation. PML/RAR␣ fusion gene, the portion of the PML gene associa- Heim et al21 reported another case without involvement of ted with the RARA␣/PML fusion and detected by the probe 17q with a t(3;15)(q21;q22). Subsequently, molecular and in was translocated to 9q34. No chimeric RAR␣/PML fusion situ hybridization studies of both patients demonstrated an gene was detected. A total of 25 cells were examined. Five absolute requirement for the rearrangement of the fusion of cells were cytogenetically normal (46,XX). The cytogenetic RAR␣/PML and PML/RAR␣ gene in the leukemogenesis of findings based on new nomenclature58 by FISH techniques APL.26 Recently, Arranz et al28 identified an additional clone APL without RAR␣/PML gene rearrangement SK Gogineni et al 516

Figure 1 Diagrammatic representation of complex translocations [der(9)t(1;9)(q25;q34), der(9)t(9;17;15)(q34;q11;q22)], as revealed by FISH technique

t(6;17) besides t(15;17) involving band 17q21 without a RAR␣ Acknowledgements rearrangement in the t(6;17) translocation. Molecular cytogenetic findings of our case clearly demon- We would like to thank Michael J Macera for valuable sugges- strated that the PML gene was translocated to chromosome 9; tions, Robert Robinson for the photography, Robert A Conte not to chromosome 17, lacking this unique fusion with RAR␣ for proofreading and Mark AR Sealy for typesetting the gene. Obviously, this occult rearrangement has created con- manuscript. fusion concerning the mechanism of carcinogenesis of APL. Is the PML gene an essential component of leukemogenesis in APL? A concise summary of previously reported cases where a References barrage of conflicting views have been debated is presented in Table 1. It has further been suggested that there is no dis- 1 Golomb HM, Rowley JD, Vardiman J, Baron J, Locker G, Krasnow S. Partial deletion of long arm of chromosome 17. A specific tinction between the patients with variant translo- abnormality in acute promyelocytic leukemia? Arch Int Med 1976; 32,37,41,46 47 cation and those with an atypical translocation. 136: 825–828. Atypical APL without t(15;17) and with the PML/RAR␣ and 2 Rowley JD, Golomb HM, Dougherty C. (15;17) translocation, a RAR␣/PML fusion transcripts has been reported suggested that consistent chromosomal change in acute promyelocytic leukemia. rearrangement at the molecular level has occurred. After an Lancet 1977; 1: 549–550. 3 Pandolfi PP, Alcalay M, Longo L, Fagioli M, Zangrilli D, Grignani extensive review search it was concluded that APL can be F, Menccarelli A, Biondi A, Rambaldi A, LoCoco F, Grignani F, considered as an unique entity within AML whose genetic Pelicci PG. Molecular genetics of the t(15;17) of acute promyelo- basis is quite intriguing.48–57,59–61,69,70 The molecular charac- cytic leukemia (APPL). 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