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Acute Myelogenous Leukemia with dup(1)(p22p36),dup(l_)(p22p36): A Novel Case?

Sarah Porter, Andrew M. Walker, T. Andrew Lister, Eric J. Watts, and Debra M. Lillington

ABSTRACT: A case of acute myelogenous leukemia (AML) French-American-British (FAB)-type M5b is described, secondary to myelodysplastic syndrome (MDS), in which a primary clone containing a dup (1)(13221336) and a subclone containhlg dup(1)(p22p36), dup( l_)(p22p36), were identified. This is believed to be a novel mutation in AML.

INTRODUCTION

Abnormalities affecting chromosome lp are well docu- mented in neoplastic disease, mainly as translocations or deletions leading to loss of heterozygosity (LOH). Recur- rent translocations involving chromosome lp36 are well recognized in acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) and, in particular, the t(1;3)(p36;q21) and t(1;17)(p36;q12-21) are associated with AML cases in which there is a preceding MDS. The t(1;12)(p36;p12) also involving lp36 occurs in AML M5a [1]. We report a partial duplication of chromosome lp occurring in both homologues in a case of AML M5b sec- ondary to MDS.

CASE REPORT

The patient was a 65-year-old man who first presented to his general practitioner with erythema, which was diag- nosed as acral vasculitis. A complete blood count showed mild anemia and in particular neutropenia [hemoglobin level (Hb) 9.1 g/dl, white blood cell (WBC) count 3.1 x 10S/L, and platelet count 273 x 109/L]. The patient was then referred to Basildon Hospital. A bone marrow (BM) biopsy was normocellular and showed active hematopoie- sis with dysplastic erythropoiesis. The iron stain showed many ringed sideroblasts. Cytogenetic studies were not undertaken at that time. The patient was treated with pyri- doxine and folic acid, but showed no improvement; 6

From the ICRF Department of Medical Oncology, St. Bartho- lomew's Hospital, London (S. P., A. M. W., T. A. L., D. M. W.); and the Department of Haematology, Basildon Hospital (E. J. W.), Essex, England.

Address reprint requests to: D. S. Porter, ICRF Department of Medical Oncology, 3rd Floor, Science Building, St. Bartholomew's Hospital Medical College, Charterhouse Square, London ECIM 6BQ.

Received June 5,1995; accepted September 1, 1995

Cancer Genet Cytogenet 87:48-51 (1996) © Elsevier Science Inc., 1996 655 Avenue of the Americas, New York, NY 10010

months after referral, he became strongly transfusion- dependent and developed cellulitis, weight loss, anorexia, infections, and headaches. Progression to AML was diag- nosed, and he was referred to St. Bartholomew's Hospital for disease management.

Clinical examination showed the patient to have bilat- eral cervical lymphadenopathy. Complete blood count (Hb 12.2 g/dl, WBC 6.2 x 109/L, neutrophils 0.1 x 10S/L, plate- let count 14 x 109/L) and BM biopsy (Hb 1.4 g/dl, WBC 1.1 x 109/L, neutrophils 1.0 × 109/L, platelet count 4 x 10S/L, with > 70% blasts) were undertaken, and a diagno- sis of AML M5b was made. The BM was cultured for cyto- genetic analysis, and the patient was subsequently treated with mitoxantrone and cytosine arabinoside. The cell count never recovered after the first cycle of treatment, and the patient died 4 weeks later after a cerebrovascular accident.

Cytogenetic and Fluorescence In Situ Hybridization (FISH) Analysis Cytogenetic analysis by GTG-banding showed 65% of cells to be normal, with 25% consisting of a mainline clone with dup(1)(p22p36) as the sole abnormality, (Fig. 1) and 10% comprising a subclone with both homologues of chromosome 1 carrying an identical duplication (46,XY, dup(1)(p22p36), dup(1)(p22p36)) (Fig. 2). The two homo- logues could be distinguished by variation in the hetero- chromatic region at lq12 (Fig. 3). FISH with a whole chromosome 1 paint (Cambio) confirmed that the addi- tional material was derived from chromosome 1.

DISCUSSION

Abnormalities of chromosome 1 occur nonrandomly in several malignancies, including MDS and AML. They con- stitute the most common karyotypic alterations in cervical carcinomas, frequently including deletions in the region

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Acute Myelogenous Leukemia wi th dup(1)(p22p36),dup(1)(p22p36) 49

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Figure I Karyotype of the mainline clone (chromosomes 1 indicated by arrows). *Abnormal homologue. The homologue with the paler heterochromatic region at lq12 carries the primary duplication.

of 1p32-p36 [2:-4]. Other chromosome l p abnormal i t ies also occur in colorectal adenomas and carcinomas [5] and mul t ip le endocr ine neoplas ia- type 2 (MEN-2) heredi tary syndromes [6].

Dupl icat ion of chromosome 1p22-p36 as a pr imary or secondary leukemogenic mechan i sm can only be specu- la ted on, a l though several oncogenes and growth factor receptor genes are known to map to this region, which may have been d i s rup ted or ampli f ied by the part ia l dupl i - cation. The human granttlocyte colony-s t imulat ing factor receptor gene (CSF3R) maps to lp34 .3-35; this is a glyco- prote in that regulates proliferat ion, differentiation, and matura t ion of cells of the neut rophi l ic granulocyt ic l in- eage [7]. DNA sequences for spe rmid ine synthase, which is essential for the regulat ion of cell growth and differenti- ation, map to 1p22-p36 [8]. Oncogenes known to map to this region of interest in~.lude C-SRC to band 1p34-p36, B-LYM-1, and L-MYC to band lp32 and JUN to band 1p31-p32 [9]. It is also of interest that there are common aphid icol in-sens i t ive fragile sites at both l p36 (FRAIA) and lp22 (FRAID) [10], a l though there was no evidence of fragility in any of the cells. It is most unusua l to f ind an ident ica l dupl ica t ion on two different homologues of a chromosome; certainly, "we know of no other repor ted

cases of this dupl ica t ion in ei ther MDS or AML (all French-American-Bri t i sh types), and wou ld be interested to hear of any future occurrences.

REFERENCES

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4. Skreekantaiah C, De Braekeleer M, Haas O (1991): Cytoge- netic findings in cervical carcinoma. Cancer Genet Cytogenet 53:75-81.

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7. Inazawa J, Fukunaga R, Seto Y, Nakagawa H, Misawa S, Abe

50 S. Porter et al.

F igure 2 Karyotype of the subclone (chromosomes 1 indicated by arrows). Both homologues carry an identical duplication.

Figure 3 Karyotype of the normal cell line (chromosomes 1 indicated by arrows). The difference in the hetero- chromatic region between the homologues is clearly apparent.

Acute Myelogenous Leukemia with dup(1)(p22p36),dup(1)(p22p36) 51

T, Nagata S (1991): Assignment of the human granulocyte colony stimulating factor receptor gene (CSF3R) to chromo- some 1 at region p35-p34.3. Abstracts for the Committee on the Genetic Constitution of Chromosome 1. Cytogenet Cell Genet 58:1850-1867.

8. Winqvist R, Alanen L, Grzeschik KH, J~inne J, Eloranta T (1991): Mapping of DNA sequences for spermidine synthase to human chromosome 1p36-p22 and chromosome 3p14-

q21. Abstracts for the Committee on the Genetic Constitution of Chromosome 1. Cytogenet Cell Genet 58:1850-1867.

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10. Sutherland GR, Hecht F (1985): Fragile sites on human chro- mosomes. Oxford monograph on medical genetics-13. O.U.P., New York.