Frequent deletion of hSNF5/INI1, a component of the SWI/SNF complex, in chronic myeloid leukemia

During routine two-fusion fluorescence in situ hybridization analysis of pa tients with blast crisis of chronic myeloid leukemia (CML), we observed tha t yeast artificial chromosome 29GD7, which is distal to BCR at 22q11, faile d to hybridize to the 9q+ derivative chromosome in 3 of 11 (27%) cases. Thi s deleted region is close to hSNF5/INI1 (SMARCB1), a gene that encodes a wi dely expressed component of the SWI/SNF chromatin remodeling complex and th at suffers biallelic mutations in malignant rhabdoid tumors. To determine w hether hSNF5/INI1 was also deleted in patients with CML, we performed fluor escence in situ hybridization analysis with a specific cosmid probe. Deleti on of hSNF5/INI1 on the 9q+ chromosome was found in 9 of 25 (36%) eases in blast crisis (lymphoid, n = 3; myeloid, n = 6). For the three of these nine patients for whom material mas available prior to transformation, deletion s were also seen in chronic phase, indicating that they are early events, A nalysis of an additional 21 patients in chronic phase revealed heterozygous loss of hSNF5/INI1 in 5 (24%) Eases, Of the 14 patients who had hSNF5/INI1 deletions, 7 showed a mosaic pattern of hybridization in which only a prop ortion of CML cells that harbored both the t(9;22) derivative chromosomes h ad a deletion, indicating that loss of hSNF5/INI1 was acquired during the c ourse of the disease, Single-strand conformation polymorphism analysis of a ll nine hSNF5/INI1 exons and splice junctions failed to reveal any mutation s for 31 patients in transformation, including 8 who had deletions, althoug h two polymorphisms were identified. We conclude that deletions of hSNF5/IN I1 are frequent in patients with CML. Such deletions may be associated with reduced levels of hSNF5/INI1 expression, which could contribute to leukemo genesis by altering chromatin-mediated transcriptional control. Alternative ly, the deletions could target another unidentified gene at 22q11 that play s a role in the pathogenesis of CML.