Hoxa9 Immortalizes a Granulocyte-Macrophage Colony-Stimulating Factor-Dependent Promyelocyte Capable of Biphenotypic Differentiation to Neutrophils or Macrophages, Independent of Enforced Meis Expression

Abstract

The genes encoding Hoxa9 and Meis1 are transcriptionally coactivated in a subset of acute myeloid leukemia (AML) in mice. In marrow reconstitution experiments, coexpression of both genes produces rapid AML, while neither gene alone generates overt leukemia. Although Hoxa9 and Meis1 can bind DNA as heterodimers, both can also heterodimerize with Pbx proteins. Thus, while their coactivation may result from the necessity to bind promoters as heterodimers, it may also result from the necessity of altering independent biochemical pathways that cooperate to generate AML, either as monomers or as heterodimers with Pbx proteins. Here we demonstrate that constitutive expression of Hoxa9 in primary murine marrow immortalizes a late myelomonocytic progenitor, preventing it from executing terminal differentiation to granulocytes or monocytes in the presence of granulocyte-macrophage colony-stimulating factor (GM- CSF

Genome profiling of acute myelomonocytic leukemia: alteration of the MYB locus in MYST3-linked cases

“…36 Constitutive expression of HOXA9 in primary murine marrow immortalizes a late myelomonocytic progenitor preventing it from executing terminal differentiation. 37 HOXA9 is also fused to NUP98 in acute leukemia with t(7;11). 38 Finally, there is a direct link between MLL alterations and HOXA9 expression.…”

Mixed-lineage-leukemia (MLL) fusion protein collaborates with Ras to induce acute leukemia through aberrant Hox expression and Raf activation

“…6 A Hoxa9-immortalized murine myelomonocytic cell line, A9G, was established through infection with retroviruses harboring Hoxa9 in pMXs/IRES-EGFP 29 as reported earlier. 32 The HF6, 6 A9G and murine pro-B Ba/F3 28 cells were cultured in the presence of interleukin-3 (IL-3) (R&D Systems, Minneapolis, MN, USA). HF6 cells transduced with FLT3 mutants were cultured in the same medium, except for the absence of IL-3.…”

HoxB8 requires its Pbx-interaction motif to block differentiation of primary myeloid progenitors and of most cell line models of myeloid differentiation

“…HoxA9 is required for normal myelopoiesis and lymphopoiesis as evidenced in HoxA9 knockout mice which are de®cient in their production of mature granulocytes and lymphocytes and show both increased apoptosis and impaired T-cell di erentiation (Izon et al, 1998). Enforced expression of HoxA9 blocks the di erentiation of myeloid progenitors capable of biphenotypic di erentiation to either neutrophils in response to G-CSF or macrophages in response to M-CSF (Calvo et al, 2000). Coactivation of HoxA9 and Meis1 transcription causes rapid AML in mice Kroon et al, 1998).…”

“…One oncogenic phenotype elicited by both Hox and E2a-Pbx1 oncoproteins is blocking hematopoietic di erentiation: enforced expression of Hox11 (Hatano et al, 1991;Hawley et al, 1994), HoxA9 (Calvo et al, 2000), HoxA10 , HoxB3 , HoxB4 (Sauvageau et al, 1995), HoxB7 (Care et al, 1999), or HoxB8 (Blatt et al, 1988;Perkins et al, 1990) prevents the di erentiation of a variety of myeloid and lymphoid progenitors. Among these Hox proteins, the importance of interaction with Pbx and Meis partners for oncogenic function has been addressed for HoxB3, HoxB4, HoxB7, and HoxA9, as well as Nup98-HoxA9, a transcriptionally activated version of HoxA9 formed by the t(7;11) translocation that fuses N-terminal sequences of Nucleoporin 98 (Nup98) to sequences just upstream of the HoxA9 Pbxinteraction motif and HD (Borrow et al, 1996;Nakamura et al, 1996).…”