Despite recent advances in the treatment of acute myeloid leukemia (AML), the morbidity and mortality of AML remains very high and novel therapeutic approaches are urgently needed. This is a competing renewal application whose overall objective is to define the functional significance of novel protein complexes in AML cells and to exploit their potential therapeutic targeting. We have identified novel regulatory protein complexes involving the cyclin dependent kinase 9 (CDK9). We found that CDK9 is a novel binding partner of the mTOR complex scaffold protein, mLST8 and is present in distinct mTOR-like (CTOR) complexes in the cytoplasm and nucleus. In the nucleus, CDK9 binds to Raptor and mLST8, forming CTORC1, to promote transcription of genes important for leukemogenesis. In the cytoplasm, CDK9 binds to Rictor, SIN1 and mLST8, forming CTORC2 complexes that control mRNA translation through phosphorylation of LARP1 and rpS6. Targeting CTOR complexes results in suppression of growth of primary human AML progenitors in vitro and generation strong antileukemic responses in AML xenografts in vivo, suggesting an essential role for CTOR complexes in the survival of AML leukemic precursors.
Specific aim 1 will define the functions of nuclear CTORC1 complexes and mechanisms by which they control expression of genes that promote leukemogenesis. Studies will be performed to map the interactions between CDK9 and other CTORC1 elements and define mechanisms by which CTORC1 complexes control transcriptional activation of mitogenic genes and mRNA splicing.
Specific Aim 2 will determine the functions of CTORC2 complexes and their roles in mRNA translation of target genes and survival of primitive leukemic precursors. Experiments will be performed to define components and effectors of CTORC2 complexes and their roles in mRNA translation, protein expression, and leukemic cell survival.
Specific aim 3 will examine the antileukemic properties of CTORC1 and CTORC2 targeting on primary leukemic precursors in vitro and in vivo. It will involve in vitro studies using primary leukemic progenitors from a large group of AML patients and in vivo experiments using AML mouse models, all aimed to determine the impact of the different CTOR complexes on leukemogenesis and the potential synergistic effects of CTORC targeting with other antileukemic agents. Altogether, the studies of this competing renewal application will advance our understanding of the mechanisms of leukemogenesis and will provide the basis for important future clinical-translational efforts, involving targeting of CTOR complexes for the treatment of AML.
Acute myeloid leukemia (AML) is a disease with very high morbidity and mortality and new therapeutic strategies are urgently needed. The work of this proposal should have a major impact in this research area and result in the development of novel therapeutic agents for the treatment of AML by targeting unique protein complexes (CTORC complexes) that we recently identified. It can also lead to the development of new strategies combining standard chemotherapy with CTORC targeting agents for the treatment of AML.
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