The long-term goal of our lab is to understand the role of the Core Binding Factor (CBF) family of transcription factors in acute myeloid leukemia (AML). CBF family members, which include RUNX1 and its binding partner CBFB, are the most frequently mutated genes in leukemia. One of the most common recurrent CBF mutations is the fusion gene CBFB-MYH11 (CM), which is generated by of the inversion of chromosome 16 [inv(16)]. Expression of CM is the initiating event in AML development, but additional cooperating mutations, such as activating mutations in the tyrosine kinase KIT, are required for transformation to a frank leukemia. CM is assumed to also be required after the acquisition of cooperating mutations, but its role during leukemia maintenance is currently poorly understood. CM was originally thought to dominantly repress RUNX1, leading to the repression of tumor suppressor genes. Our recent work supports a new model of the fusion protein?s activity: CM and RUNX1 together activate transcription of pro-leukemic genes. This new model implies that identifying the functionally important targets genes of the fusion protein complex may lead to new potential drug targets. Another extension of this new model is that there may be additional co-factors required for CM?s transcriptional activity. In recent work, we found that Histone Deacetylase 1 (HDAC1) is part of the CM/RUNX1 complex, and is required for expression of CM target genes. Using a mouse model of inv(16) AML, we found that the HDAC1 inhibitor entinostat induced differentiation, and reduced leukemic burden in vivo. Based on our previous work, we hypothesize that CM is required for the expression of genes that promote leukemia maintenance, and that HDAC1 is an important co-factor of CM. Consequently, we propose that HDAC1 inhibitors will be particularly useful for the treatment of inv(16) AML.
In Specific Aim 1, we will use two complimentary approaches to define the role of CM in leukemia maintenance: a new knockin mouse model that allows for deletion of the fusion gene after leukemia development, and an inducible shRNA knockdown model. We will use these tools to determine CM?s role during leukemia maintenance in vivo, if CM independent cells can give rise to relapse, and test the role of candidate CM target genes in leukemia maintenance.
In Specific Aim 2, we will determine the requirement for HDAC1 in CM+ leukemia cells, test whether HDAC1 affects expression of both CM target and non-target genes, and test potential mechanisms for HDAC1?s non-canonical role in transcriptional activation.
Specific Aim 3 will test the potential of the entinostat to treat inv(16) AML. We will use genetic and patient derived xenograft mouse models to test whether the addition of entinostat to the standard treatments will reduce leukemic burden and increase survival. We will also test whether using entinostat to inhibit CM in combination with dasatinib to inhibit cooperating mutations in KIT is more effective than either drug alone. The proposed studies are based on our accumulated experience and our strong preliminary findings, and will address important gaps in the field and have direct translational implications for inv(16) AML patients.

Public Health Relevance

Acute Myeloid Leukemia (AML) is a cancer of the immature myeloid cells of the bone marrow. Current treatments are associated with significant, even life threatening, side effects. This project will define the role of the CBFB-MYH11 oncogene and its co-factor HDAC1 in regulating leukemia maintenance, and test whether inhibitors of these proteins have the potential to cure CBFB-MYH11 driven AML. Successful completion of this project will provide important new insights into the biology of leukemia cells and lead to significant improvements in the treatment of AML.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Klauzinska, Malgorzata
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University of Nebraska Medical Center
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