Targeting Hexosamine Biosynthetic Pathway and O-GlcNAcylation to Treat Acute Myeloid Leukemia

Louis Stokes Cleveland Va Medical Center, Cleveland OH

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Abstract

Acute myeloid leukemia (AML), is the most common form of acute leukemia in adults with poor prognosis and a high relapse rate and is considered as a “presumptive disease under code 7703” for veterans. AML is increasing in prevalence in both active duty personnel and Veterans. The survival rate of Veterans aged 65 or older with AML is less than 5%, which is significantly lower overall survival than the non-Veteran population, a difference that may reflect active duty exposure to carcinogens and ionizing radiations. There is no effective treatment for AML and current mainstay therapies fail to achieve durable remission, and over 50% of patients relapse. A main reason for AML relapse is the escape of leukemia initiating cells (LICs) from chemotherapy. Thus, there is an unmet need for new approaches to understand and treat AML. Cancer cells including AML consume high glucose for their enhanced energy needs and growth. This increased glucose flux results in enhanced activation of the hexosamine biosynthetic pathway (HBP), production of UDP-GlcNAc and increased O-GlcNAcylation of intracellular proteins. Dr. Ramakrishnan found that O-GlcNAcylation and the expression of HBP enzymes are increased in AML patient cells and that HBP inhibition kills AML cells while sparing normal cells. HBP proteins were found upregulated in AML-LICs that may contribute to relapse. Based on this, current proposal focuses on the novel overarching hypotheses that HBP activation and O-GlcNAcylation is critical for AML cell survival and relapse and targeting this pathway could selectively kill AML cells. The aims of this study include: (1). Examine the role of HBP and O-GlcNAcylation in bulk AML and AML-LICs and the effect of HBP inhibition in AML survival using leukemia cells isolated from Veteran AML patients, (2) Developing preclinical AML disease mouse models using AML patient samples to define novel disease mechanisms and evaluate the efficiency of HBP inhibition to control AML, (3) Identification of the role of specific O-GlcNAcylated proteins in AML as novel therapeutic targets and develop tools targeting O- GlcNAcylated proteins to treat AML. Targeting HBP and identifying specific O-GlcNAcylated proteins as defined novel players in AML may prove effective in controlling both progress and relapse of AML and aid future development of improved therapeutics. This study will also lay the foundation to reveal the role of HBP in other cancers (prostate, colon, lung) with increased HBP/O-GlcNAcylation that are important challenges to the VA Healthcare System.