HETEROGENEITY IN CBF-BETA MYH11 FUSION MESSAGES ENCODED BY THE INV(16)(P13Q22) AND THE T(16-16)(P13-Q22) IN ACUTE MYELOGENOUS LEUKEMIA/

Citation
Sa. Shurtleff et al., HETEROGENEITY IN CBF-BETA MYH11 FUSION MESSAGES ENCODED BY THE INV(16)(P13Q22) AND THE T(16-16)(P13-Q22) IN ACUTE MYELOGENOUS LEUKEMIA/, Blood, 85(12), 1995, pp. 3695-3703
Citations number
25
Categorie Soggetti
Hematology
Journal title
BloodACNP
ISSN journal
00064971
Volume
85
Issue
12
Year of publication
1995
Pages
3695 - 3703
Database
ISI
SICI code
0006-4971(1995)85:12<3695:HICMFM>2.0.ZU;2-7
Abstract
Inv(16)(p13q22) is one of the most frequent chromosomal rearrangements found in acute myelogenous leukemia (AML), representing approximately 16% of documented karyotypic abnormalities. The inv(16) breakpoints h ave been cloned and shown to involve the non-DNA binding component of the AML-1 transcription factor complex termed core binding factor beta gene (CBF beta) on 16q and the smooth muscle myosin heavy chain gene (MYH11) on 16p. In this study, we analyzed 37 cases of inv(16)-contain ing AML and 4 cases with t(16;16)(p13;q22) for expression of the CBF b eta/MYH11 chimeric message by reverse transcription-polymerase chain r eaction (PCR) analysis. CBF beta/MYH11 chimeric messages were detected in 33 of 37 cases with the inv(16) and in the 4 t(16;16)-containing c ases. Sequence analysis of PCR products showed extensive breakpoint he terogeneity in both CBF beta and MYH11. In addition to the previously described breakpoint in CBF beta at nucleotide (nt) 495 (amino acid 16 5), we have identified a second novel fusion point at nt 399 (amino ac id 133) in 7% of the cases. Similarly, a unique breakpoint site was id entified in MYH11 at nt 1098, as well as at three previously character ized sites at nts 994, 1201, and 1921. Of the 4 PCR-negative cases, 2 of 3 tested lacked CBF beta rearrangements by Southern blot analysis, suggesting the possible involvement of a different genomic locus in so me cases with cytogenetic evidence of inv(16). To assess whether the p ortions of CBF beta contained within the CBF beta/MYH11 chimeric produ cts retain the ability to interact with their heterodimeric DNA-bindin g partner AML-1, we performed in vitro DNA-binding analysis. Recombina nt CBF beta polypeptides consisting of the N-terminal 165 amino acids retained their ability to interact with AML-1, whereas mutants contain ing only the N-terminal 133 amino acids interacted with AML-1 less eff iciently. These data suggest that different CBF beta/MYH11 products ma y vary subtly in their biologic activities. (C) 1995 by The American S ociety of Hematology.