Frequent co-expression of the HOXA9 and MEIS1 homeobox genes in human myeloid leukemias

Abstract

There is increasing evidence that HOX homeobox genes play a role in leukemogenesis. Recent studies have demonstrated that enforced co-expression of HOXA9 and MEIS1 in murine marrow leads to rapid development of myeloid leukemia, and that these proteins exhibit cooperative DNA binding. However, it is unclear whether co-activation of HOXA9 and MEIS genes is a common occurrence in human leukemias. We surveyed expression of HOXA9 and MEIS1 in 24 leukemic cell lines and 80 patient samples, using RNase protection analyses and immunohistochemistry. We demonstrate that the expression of HOXA9 and MEIS1 in leukemia cells is uniquely myeloid, and that these genes are commonly co-expressed in myeloid cell lines and in samples of acute myelogenous leukemia (AML) of all subtypes except in promyelocytic leukemia. While HOXA9 is expressed in most cases of chronic myelogenous leukemia, MEIS1 is weakly expressed or not at all. Immunohistochemical staining of selected AML samples showed moderate to high levels of HOXA9 protein, primarily cytoplasmic, in leukemic myeloblasts, with weaker and primarily nuclear staining for MEIS1. These data support the concept that co-activation of HOXA9 and MEIS1 is a common event in AML, and may represent a common pathway of many different oncogenic mutations.

Hox genes in hematopoiesis and leukemogenesis

“…The unequivocal role of Hox genes in the pathogenesis of acute leukemia A central role for HOX genes in hematological malignancies is supported by the frequently observed elevation of HOX and MEIS1 gene expression in AML patient samples (Golub et al, 1999;Kawagoe et al, 1999;Lawrence et al, 1999;Afonja et al, 2000;Drabkin et al, 2002). Indeed, HOXA9 is the single most highly correlated gene (out of 6817) for poor prognosis in AML (Golub et al, 1999).…”

Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia

“…[50][51][52][53][54] Several LAAs have also been implicated in the multi-step leukemic transformation of hematopoietic progenitor cells, for example, ETO/MTG8, 55 hTERT 56 and the homeobox protein HOXA9. 57 The LAA WT1 may contribute to leukemogenesis by interfering with normal hematopoietic progenitor cell differentiation, which is considered as one of the first critical steps in the leukemic transformation of these cells. 16 In a transgenic mouse model, Nishida et al 50 also demonstrated the capacity of WT1 to induce leukemia in collaboration with the t(8;21) fusion protein AML1-ETO.…”

Histone deacetylase inhibitors deplete enhancer of zeste 2 and associated polycomb repressive complex 2 proteins in human acute leukemia cells

“…HOXA9 is the most frequent partner in a fusion oncoprotein with Nup98 (Nup98-HOXA9), resulting from the chromosomal translocation t(7;11)(p15;p15) observed in human leukemia (26 -28). HOXA9 is also known to interact with myeloid ecotropic viral integration site 1 homologue (MEIS1), a member of the three -amino acid loop extension subclass of homeodomaincontaining proteins (29). The MEIS1-HOXA9 interaction has been reported to rapidly accelerate leukemogenesis in mice (30 -32), making these proteins and their interaction a potential therapeutic target for further evaluation.…”