Role of a Novel Homeobox Transcription Factor (HLX) in Acute Myeloid Leukemia

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant): Despite the established use and optimization of polychemotherapy and the development of new agents that transiently reduce the tumor burden, relapse continues to be the most common cause of death in acute myeloid leukemia (AML). Less than one third of patients with AML achieve durable remission with current treatment regimens, and prognostication and risk stratification remain challenging. New targets need to be identified for more effective and individualized therapeutic intervention. We have recently reported that a non- clustered homeobox gene, HLX, is overexpressed in leukemic stem cells in a mouse AML model and in the vast majority (87%) of AML patients, including in sorted stem cells, and that higher HLX levels are independently associated with poor overall survival of AML patients. Functional studies showed that HLX overexpression leads to the formation of aberrant progenitors with blocked differentiation and unlimited serial clonogenicity, and that HLX knockdown has an inhibitory effect on AML cell growth in vitro and in vivo. However, the mechanism of action of HLX, its downstream pathways, and its role in leukemia initiation and maintenance are unknown. Based on our findings and preliminary data we hypothesize that HLX overexpression is an early step in AML pathogenesis and that HLX acts in concert with other common disease alleles, including FLT3-ITD and CBFB-MYH11, and through specific HLX-dependent pathways, including PAK1 and BTG1. We further hypothesize that HLX directly transcriptionally regulates target genes in AML, and that targeting HLX or functionally critical downstream pathways is a suitable, novel approach for the inhibition of AML. Our specific research aims are: 1) To study the role of HLX overexpression in the initiation of AML, including the ability of HLX overexpression to cooperate with other disease alleles; 2) To investigate the effect of reducing HLX expression on AML maintenance in vivo; 3) To identify functionally relevant, direct transcriptional targets of HLX in AML. We will study leukemic transformation by HLX overexpression in concert with cofactors, including FLT3ITD and CBFB-MYH11, using retroviral co-expression/transplantation assays, as well as a newly developed conditional Hlx knockin mouse model. We will study the anti-leukemic effects of HLX inhibition in primary human AML cells and a genetic mouse model of AML, and identify functionally critical pathways which mediate the leukemia-inhibitory effect of HLX downregulation. We will study whether HLX directly regulates transcription of candidate downstream genes PAK1 and BTG1. In addition, we will determine genome-wide HLX-chromatin interactions by ChIP-seq, and identify new HLX-regulated targets and test for functional relevance in AML. In summary, based on our initial discovery this study will investigate the function of HLX in AML pathogenesis, and how HLX downregulation can be utilized to inhibit leukemia. The results of this study will enhance our knowledge of disease-causing mechanisms in AML, and define HLX and its downstream pathways as novel targets for therapy in AML.
StatusFinished
Effective start/end date4/1/143/31/15

Funding

  • National Cancer Institute: $372,812.00

ASJC

  • Molecular Medicine
  • Hematology
  • Oncology
  • Cancer Research
  • Pharmacology

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