Homeodomain Expression in AML and T-ALL Cell Lines.

Abstract

HOX genes are frequent targets of chromosomal translocations and retroviral integrations in human and murine acute leukemia, often involving genes at the 5′-end of the HOX clusters. We previously reported that HOX expression patterns in AML were related to prognostic cytogenetic subsets. We also identified a distinct subset of patients with intermediate cytogenetics based on high levels of HOX and FLT3 expression, frequent FLT3 mutations and a low incidence of C/EBPa mutations. Certain cases of T-ALL also have rearrangements of homeodomain genes and some T-ALLs express limited myeloid markers. To further explore the spectrum of homeodomain gene expression, we developed qRT-PCR assays for nearly all clustered HOXA-D genes, selected homeodomain genes on chromosomes often altered in AML, and selected polycomb (Pc) genes, FLT3 and MLL. Altogether, 52 genes were analyzed in 32 AML and T-ALL cell lines. FLT3 expression was confined to a subset of AMLs. HOX11, HOX11L2 and NKX2.5 were expressed only in cases involving rearrangements of these genes. The Pc and MLL genes were uniformly expressed. Among HOX clusters, the frequency of gene expression was HOXA>B>C>D. Genes more highly expressed in the HOXC and D clusters were those at the 5′-ends (e.g., D13, C10). Marked or selective overexpression of individual genes suggests their possible involvement in the disease process, immortalization or differentiation. Examples include EN1 (SUPT1), D13 (MEGA1, B9 (PEER). A hierarchical cluster analysis based on homeodomain genes successfully identified subsets of related cell lines. Thus, the analysis of quantitative HOX expression may provide an important new tool to better understand the biology of acute leukemia.