Japanese Journal of Clinical Oncology 32:35-36 (2002)
© 2002 Foundation for Promotion of Cancer Research
De Novo Appearance of t(7;13)(q10;q33) in the Leukemic Phase of Myelodysplastic Syndrome: a Case Report
First Department of Internal Medicine, Chromosome Unit, Central Laboratory, Tokyo Medical University, Tokyo, Japan
 |
ABSTRACT |
|---|
 TOP ABSTRACT CASE REPORTDISCUSSIONREFERENCES |
|---|
Clonal cytogenetic abnormalities are found in about 50% of all patients with myelodysplastic syndrome (MDS) and the clinical implication of these abnormalities is now well documented. However, the de novo appearance of balanced translocations in MDS patients during the progression of the disease is rarely reported and the significance of the balanced translocation remain to be elucidated. We report here the first case of refractory anemia with excess blasts in transformation (RAEBt), in which a new chromosomal translocation, t(7;13)(q10;q33) appeared de novo in the AML phase. It has been revealed that rearrangements and deletions of chromosome 7, i.e. der(1;7)(q10;p10), are very complex and that multiple regions may contribute to the disease phenotype and progression. Our case suggests that the chromosomal region at 7q10, rather than 1p10, might be one of the hot spots for myeloid proliferative disorders, including MDS.
|
CASE REPORT |
|---|
|
TOPABSTRACTCASE REPORTDISCUSSIONREFERENCES |
|---|
A 70-year-old male was referred to our hospital suffering from fatigue in July 1999. He had no prior history of exposure to ionizing radiation or myelotoxic agents. Hematological findings showed anemia and thrombocytopenia: a hemoglobin of 67 g/dl, platelets 64 x 109/l and a white blood cell count of 15.7 x 109/l with 13% myeloblasts. Bone marrow aspirate showed a hypercellular marrow with 12% myeloblast. Morphological features of the bone marrow cells revealed trilineage dyshematopoiesis. The patient was diagnosed as having RAEBt based on the percentage of blast cells in the peripheral blood and the presence of Auer rods (1). A cytogenetic examination of the bone marrow cells at the phase of MDS diagnosis revealed a normal male karyotype (12/12 cells). He was treated with idarubicin and cytarabine followed by granulocyte-colony stimulating factor (G-CSF) based on the protocol established by the Japan Adult Leukemia Study Group (JALSG), but this therapy failed to induce a complete remission. The patient was then treated with CAG therapy (low-dose cytarabine, aclarubicin and G-CSF) (2), which resulted in complete remission. The patient remained in complete remission by repeated CAG therapy until February 2000.
In February 2000, the patient showed thrombocytopenia with the appearance of myeloblast (20%) in the blood. A bone marrow aspiration revealed an increasing number of myeloblasts (16%) and monoblasts (19.2%). The leukemic cells were positive for CD13, CD33, CD34 and HLA-DR antigens, but negative for 
-naphthol chloacetate esterase, which is compatible with the criteria for AML-M2. A cytogenetic analysis of the bone marrow cells revealed 45,XY,t(7;13)(q10;q33),–16 [15/21 cells]/46, XY [6/21 cells] (Fig. 1). Although the patient was treated with multiple regimens, the disease deteriorated and the patient died from complications of bone marrow failure and pneumonia in July 2000.
|
|
DISCUSSION |
|---|
|
TOPABSTRACTCASE REPORTDISCUSSIONREFERENCES |
|---|
Our RAEBt patient showed a new chromosomal translocation (7;13)(q10;q33) that appeared de novo in the AML phase. We could not find a report of any similar translocations between the 7q10 and 13q33 among t(7;13) cases in neoplasm. Chromosomal abnormality in MDS patients is one of the major factors predicting their prognoses. An accumulation of data on MDS patients from many nations throughout the world made it possible to determine prognostic factors and provided important information concerning leukemic transformation in MDS patients, i.e. IPSS (3). This study pointed out the clinical relevance of cytogenetic results in MDS patients to provide additional and important information concerning their prognosis. According to the IPSS, normal karyotypes in MDS patients are considered to be a factor for favorable prognosis (3). However, little is known about additional cytogenetic changes in MDS patients during the process of disease progression. De Souza Fernandez et al. (4) reported cytogenetic changes in 127 MDS patients and 24% of them had disease progression; only eight (33.3% of MDS patients with disease progression) had acquisition of chromosome alterations. Of the MDS patients with additional cytogenetic changes, they found translocations between chromosomes 1 and 8 or 7 and 17 (4).
Chromosomal breakage at 7q10 is frequently found in MDS or chronic myeloid proliferative disorders as a result of unbalanced der(1;7)(q10;p10) (5,6). Recent studies have revealed that rearrangements and deletions of chromosome 7 are very complex and that multiple regions may contribute to the disease phenotype and progression (7,8). One interpretation of a de novo appearance of a 7q10 abnormality in hematological neoplasias is that it might be due to karyotypic evolution (9,10). It has been reported that a close relationship existed between G-CSF and therapy-related MDS associated with monosomy 7 and that G-CSF might have played a role in the development of abnormal clone (11). Because our case had been administered a low total dose of 210 µg/kg over 8 months, administration of G-CS might be related to the karyotypic evolution. Although we failed to detect any chromosomal change at 7q10 at the time of MDS diagnosis, the most plausible explanation for the de novo appearance of t(7;13) is that it might be due to the clonal expansion of leukemic stem cells that resist chemotherapy, since the AML transformation with a novel chromosomal translocation appeared very rapidly in this case.
On the other hand, genetic mapping of between 13q33 and q35 region has several candidate genes, which may be affected in the t(7;13)(q10;q33) in our case. These include genes encoding FGF 14 (fibroblast growth factor 14), TNFSF13B (tumor necrosis factor ligand superfamily) and RASA3 (RAS p21 protein activator, member 13B). The protein encoded by the FGF 14 gene is a member of the fibroblast growth factor (FGF) family. FGF family members comprise broad mitogenic and cell survival activities and are involved in various biological processes such as embryonic development, cell growth, tissue repair, tumor growth and invasion (12). FGF signaling is generally assumed to occur by activation of transmembrane tyrosine kinase receptors. The significance of FGF 14 translocation, however, is unclear. Constitutive activation and/or alternation of the FGF signaling may provide one possible mechanism of AML transformation in our case.
The discovery of a novel t(7;13)(q10;q33) resulting in AML transformation may provide new insight in leukemogenesis. It has been revealed that rearrangements and deletions of chromosome 7, i.e. unbalanced der(1;7)(q10;p10), are very complex and that multiple regions may contribute to the disease phenotype and poor prognosis. Our case further suggests that the chromosomal region at 7q10, rather than 1p10, might be one of the hot spots for myeloid proliferative disorders, including MDS.
|
FOOTNOTES |
|---|
+ For reprints and all correspondence: Goro Sashida, First Department of Internal Medicine, Tokyo Medical University, 6–7–1 Nishi-shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan. E-mail: yub@dd.iij4u.or.jp
|
REFERENCES |
|---|
|
TOPABSTRACTCASE REPORTDISCUSSIONREFERENCES |
|---|
1 Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnick HR, et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 1982;51:189–99.[Web of Science][Medline]
2 Yamada K, Furusawa S, Saito K, Waga K, Koike T, Arimura H, et al. Concurrent use of granulocyte colony-stimulating factor with low-dose cytosine arabinoside and aclarubicin for previously treated acute myelogenous leukemia: a pilot study. Leukemia 1995;9:10–4.[Web of Science][Medline]
3
Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997;89:2079–88.
4 de Souza Fernandez T, Ornellas MH, Otero de Carvalho L, Tabak D, Abdelhay E. Chromosomal alterations associated with evolution from myelodysplastic syndrome to acute myeloid leukemia. Leuk Res 2000;24:839–48.[Web of Science][Medline]
5 Horiike S, Taniwaki T, Misawa S, Nishigaki H, Okuda T, Yokota S, et al. The unbalanced 1;7 translocation in de novo myelodysplastic syndrome and its clinical implication. Cancer 1990;65:1350–4.[Web of Science][Medline]
6 Pedersen B. Survival of the patients with t(1;7)(p11:p11): report of two cases and review of the literature. Cancer Genet Cytogenet 1992;69:53–9.
7
Le Beau MM, Espinosa R III, Davis EM, Eisenbert JD, Larson RA, Green ED. Cytogenetic and molecular delineation of a region of chromosome 7 commonly deleted in malignant myeloid diseases. Blood 1996;88:1930–5.
8 Pedersen B, Norgaard JM, Pedersen BB, Clausen N, Rasmussen IH, Thorling K. Many unbalanced translocations show duplication of a translocation participant. Clinical and cytogenetic implications in myeloid hematologic malignancies. Am J Hemaol 2000;64:161–9.
9 Hamamoto K, Hashimoto-Ninomiya A, Kishimoto Y, Kimura T, Fujitake H, Yasunaga K, et al. Unbalanced 1;7 translocation in myelodysplastic syndrome following treatment of acute myeloblastic leukemia with an 8;21 translocation. Cancer Genet Cytogenet 1994;74:35–9.[Web of Science][Medline]
10
Liang H, Faiman J, Claxton DF, Nowell PC, Green ED, Nagarajan L. Molecular anatomy of chromosome 7q deletions in myeloid neoplasms. Evidence for multiple critical loci. Proc Natl Acad Sci USA 1998;95:3781–5.
11 Kaito K, Kobayashi M, Katayama T, Masuoka H, Shimada T, Nishiwaki K, et al. Long-term administration of G-CSF for aplastic anaemia is closely related to the early evolution of monosomy 7 MDS in adults. Br J Haematol 1998;103:297–303.[Web of Science][Medline]
12
Smallwood PM, Munoz-Sanjuan I, Tong P, Macke JP, Hendry SHC, Gilbert DJ, et al. Fibroblast growth factor (FGF) homologous factors: new members of the FGF family implicated in nervous system development. Proc Natl Acad Sci USA 1996;93:9850–7.
Received May 14, 2001; accepted October 12, 2001.
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||