Meis1, a PBX1-Related Homeobox Gene Involved in Myeloid Leukemia in BXH-2 Mice

Abstract

Leukemia results from the accumulation of multiple genetic alterations that disrupt the control mechanisms of normal growth and differentiation. The use of inbred mouse strains that develop leukemia has greatly facilitated the identification of genes that contribute to the neoplastic transformation of hematopoietic cells. BXH-2 mice develop myeloid leukemia as a result of the expression of an ecotropic murine leukemia virus that acts as an insertional mutagen to alter the expression of cellular proto-oncogenes. We report the isolation of a new locus, Meis1, that serves as a site of viral integration in 15% of the tumors arising in BXH-2 mice. Meis1 was mapped to a distinct location on proximal mouse chromosome 11, suggesting that it represents a novel locus. Analysis of somatic cell hybrids segregating human chromosomes allowed localization of MEIS1 to human chromosome 2p23-p12, in a region known to contain translocations found in human leukemias. Northern (RNA) blot analysis demonstrated that a Meis1 probe detected a 3.8-kb mRNA present in all BXH-2 tumors, whereas tumors containing integrations at the Meis1 locus expressed an additional truncated transcript. A Meis1 cDNA clone that encoded a novel member of the homeobox gene family was identified. The homeodomain of Meis1 is most closely related to those of the PBX/exd family of homeobox protein-encoding genes, suggesting that Meis1 functions in a similar fashion by cooperative binding to a distinct subset of HOX proteins. Collectively, these results indicate that altered expression of the homeobox gene Meis1 may be one of the events that lead to tumor formation in BXH-2 mice.

Transduction of the SkBr3 breast carcinoma cell line with the HOXB7 gene induces bFGF expression, increases cell proliferation and reduces growth factor dependence

“…Some murine HOX genes have been described to be able of transforming murine cells both in vivo and in vitro (Maulbecker and Gruss 1993). In humans, some divergent homeobox containing genes are involved in chromosomal translocations or their expression associated with di erent leukemias (Dedera et al, 1993;Deguchi and Kehre 1993;Hatano et al, 1991;Moskow et al, 1995).…”

“…The coordinate expression of HOX genes as described in teratocarcinoma (Mavilio 1993), activated T lymphocytes (CareÁ et al, 1994) and progenitor hematopoietic cells (Giampaolo et al, 1994;Sauvageau et al, 1994) appears to be lost in neoplasias of di erent origin (CareÁ et al, 1996;Cillo et al, 1992). The oncogenic potential of several murine Hox genes has been demonstrated by in vitro and in vivo transformation assays (Maulbecker and Gruss, 1993), while divergent human and murine homeobox containing genes such as Pbx1, tcl-3, HB24 and meisl are involved in speci®c chromosomal translocations (Dedera et al, 1993;Hatano et al, 1991) or are associated with di erent leukemias (Deguchi et al, 1993;Moskow et al, 1995).…”

Hox genes in hematopoiesis and leukemogenesis

“…The proto-oncogene Meis1 was first identified, together with Hoxa7 and Hoxa9, as a common viral integration site in myeloid leukemic cells of BXH-2 mice (Moskow et al, 1995). We and others have subsequently demonstrated that overexpression of Meis1 collaborates with multiple native and NUP98-HOX fusion genes to accelerate the onset of AML in the murine BMT models (Kroon et al, 1998Thorsteinsdottir et al, 2001;Pineault et al, 2003Pineault et al, , 2004Fischbach et al, 2005).…”

An autoinhibitory effect of the homothorax domain of Meis2

“…Mammalian Meis1 (myeloid ecotropic insertion site 1) was identified initially as a common site of viral integration in mouse myeloid leukemia cells (21), and the related Meis2 and Meis3 genes were identified by sequence similarity (22,23). Meis1 plays a key role in the progression of AML and MLL leukemia, and fusion proteins generated by chromosomal rearrangements in MLL can induce increased expression of Meis1 (24-26).…”