HoxA9 and HoxA10 control leukemia stem cell expansion by regulating FGF2

Project: Research project

Project Details

Description

Acute myeloid leukemia (AML) is a heterogeneous disease with variable response to standard chemotherapy treatment in different leukemia patients. Recent studies determined that some of this heterogeneity can be accounted for by differences in leukemia cells from different patients that can be detected at the molecular level. For example, in some forms of AML, good or poor prognosis can be predicted by the presence of specific chromosomal breaks and rearrangements. One such recurring rearrangement involves a break on chromosome 11 that results in relocation of a gene referred to as MLL to another chromosome. Such leukemias are referred to as 11q23-leukemias and are characterized by poor prognosis and resistance to treatment. Further characterization of such leukemias identified additional abnormalities at the molecular level that are consistently present with MLL gene relocation. These abnormalities include an increase in leukemia cells in a set of regulatory proteins referred to as Hox proteins.
Hox proteins have been found to control expansion, maturation and death of immature cells in the bone marrow, although exactly how Hox proteins influence these events is not established. Disordered control of Hox proteins in 11q23-AML is thought to contribute to the process of leukemia development, but the mechanisms for this are not defined. In our studies, we found that two of these Hox proteins (referred to as HoxA9 and HoxA10) control production of a critical growth factor in immature bone marrow cells. This growth factor, referred to as fibroblast growth factor 2 (Fgf2), is known to be a key regulator of hematopoietic stem cell expansion and survival.
The hypothesis of these studies is that HoxA9 and HoxA10 contribute to poor prognosis in leukemia by increasing Fgf2 production by leukemic cells in the bone marrow. We will investigate this by determining;
1. The contribution of Fgf2 to HoxA9 or HoxA10-induced expansion and/or survival of immature bone marrow cells. We will use isolated murine bone marrow cells or murine bone marrow transplantation studies for these investigations.
2. The contribution of Fgf2 to leukemia development and drug resistance in poor prognosis AML. We will use a murine model of 11q23-AML or bone marrow samples from human patients with related leukemias for these studies.
The goal of these studies is to determine if Fgf2 or the receptor for Fgf2 are rationale targets for treatment refractory, poor prognosis AML. Fgf-receptor inhibitors are in human clinical trials for solid tumors, so the results of these studies could be rapidly translated to specifically targeted human clinical trials for leukemia.
StatusFinished
Effective start/end date10/1/1312/31/17

Funding

  • Leukemia & Lymphoma Society (Agmt Signed 8/1/13 - 6006-14)

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