CBFA2(AML1) translocations with novel partner chromosomes in myeloid leukemias: association with prior therapy.
CBFA2(AML1) has emerged as a gene critical in hematopoiesis; its protein product forms the DNA-binding subunit of the heterodimeric core-binding factor (CBF) that binds to the transcriptional regulatory regions of genes, some of which are active specifically in hematopoiesis. CBFA2 forms a fusion gene with ETO and MDS1/EVI1 in translocations in myeloid leukemia and with ETV6(TEL) in the t(12;21) common in childhood pre-B acute lymphoblastic leukemia. We have analyzed samples from 30 leukemia patients who had chromosome rearrangements involving 21q22 by using fluorescence in situ hybridization (FISH). Our analysis showed that 7 of them involved CBFA2 and new translocation partners. Two patients had a t(17;21)(q11.2;q22), whereas the other 5 had translocations involving 1p36, 5q13, 12q24, 14q22, or 15q22. Five of these novel breakpoints in CBFA2 occurred in intron 6; this same intron is involved in the t(3;21). One breakpoint mapped to the t(8;21) breakpoint region in intron 5, and 1 mapped 5' to that region. All 7 CBFA2 rearrangements resulted from balanced translocations. All 7 patients had myeloid disorders (acute myeloid leukemia or myelodysplastic syndrome); 2 were de novo and 5 had treatment histories that included topoisomerase II targeting agents. The association of therapy-related disorders with translocations involving CBFA2 was significant by Fisher's exact test (P < .003). These results provide further evidence that this region of CBFA2 is susceptible to breakage in cells exposed to topoisomerase II inhibitors.
Section of Hematology/Oncology, Department of Medicine, and the Cancer Research Center, The University of Chicago Pritzker School of Medicine, Chicago, IL, USA.
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D
Roulston
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Espinosa
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Nucifora
R A
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Larson
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Le Beau
J D
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Rowley
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002877:Chromosomes, Human / Q000235:genetics / Q000648:ultrastructure*; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics / Q000648:ultrastructure; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics / Q000648:ultrastructure; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics / Q000648:ultrastructure; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics / Q000648:ultrastructure; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics / Q000648:ultrastructure; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics / Q000648:ultrastructure*; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics / Q000648:ultrastructure; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000473:pathology; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors / Q000235:genetics*; D014178:Translocation, Genetic
D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C493728:RUNX1 protein, human; D014157:Transcription Factors