Role of PGDH in leukemia pathogenesis


Principal Investigator: Michael L Cleary
Abstract: DESCRIPTION (provided by applicant): The overall objectives of the studies proposed in this application are to investigate the molecular pathways that sustain leukemia stem cells with the ultimate goal of defining novel cancer biomarkers and therapeutic targets. The proposed studies build on our recent discoveries that PGDH (NAD+-dependent 15-hydroxyprostaglandin dehydrogenase), a key enzyme involved in metabolic inactivation of prostaglandins, is implicated in the pathogenesis of a major subset of acute leukemia. It is highly expressed in leukemia stem cells, and serves as a crucial mediator in the MLL/HOX pathway that regulates leukemia stem cell self-renewal. The implicated role of PGDH is highly unexpected, as it has not previously been associated with contributing to cancer causation, which contrasts with earlier proposed protective roles. Even more unexpected, is our observation that the contributions of PGDH to leukemia pathogenesis are independent of its enzymatic activity, thus inferring that PGDH has a previously unknown non-canonical and novel biochemical function. We hypothesize that PGDH qualitatively regulates self-renewal to induce aberrant stem cell and/or progenitor expansion, a hypothesis that will be addressed in three specific aims. In Specific Aim #1, we will determine the mechanism for the non-canonical role of PGDH in leukemia pathogenesis. Using gain-of-function genetic approaches in mouse model systems, we will perform structure/function studies to identify leukemia-specific functional domains of PGDH. This will direct subsequent biochemical studies to identify proteins that specifically associate with essential domains required for PGDH oncogenic contributions. Studies in Specific Aim #2 will define the molecular pathways sustained by PGDH in leukemia stem cells using a combination of mouse models of acute leukemia as well as human leukemia cell lines and cells. The molecular pathways affected by PGDH will be characterized using high throughput expression profiling techniques, in conjunction with high-end bioinformatics to establish its role in human leukemia subtypes. In Specific Aim #3 we will define the role of PGDH in normal hematopoiesis using a genetic approach with a particular emphasis on hematopoietic stem cell maintenance and self-renewal in PGDH conditional knockout mice. A greater understanding of the non-canonical functions of PGDH in cancer versus normal stem cells will provide a unique biomarker and facilitate efforts to achieve more efficacious therapies by selectively targeting leukemia stem cells while sparing hematopoietic stem cells.
Funding Period: 2012-07-10 - 2017-04-30
more information: NIH RePORT

Top Publications

  1. pmc The AML salad bowl
    Jesús Duque-Afonso
    Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
    Cancer Cell 25:265-7. 2014

Detail Information


  1. pmc The AML salad bowl
    Jesús Duque-Afonso
    Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
    Cancer Cell 25:265-7. 2014
    ..In this issue of Cancer Cell, Klco and colleagues used whole genome sequence analysis to demonstrate the correlation of genetic clonal architecture with functional heterogeneity in acute myeloid leukemia. ..

Research Grants30

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  2. Ezh2 in MLL-AF9 mediated acute myeloid leukemia
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    ..Finally, the plan is ideally carried out in the Division of Hematology/Oncology at Children's Hospital Boston, given its distinguished record for training physician-scientists in a rich and collaborative environment. ..
  3. Role of Setbp1 in leukemic stem cell self-renewal
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  4. HSC Diversity: Regulation by Clonal Selection vs Epigenetic Induction
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    Daniel C Link; Fiscal Year: 2013
    ..Aim 2. We will define the contribution of Cxcl12 expression by osteoblasts and endothelial cells to HSC function and trafficking. ..
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  7. MicroRNA Regulation of Stem Cell Self-renewal
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  9. Targeting PML for leukemia therapy.
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    ..The elucidation of the mechanisms by which PML regulates the maintenance of the LIC pool could in turn lead to novel therapeutic approaches to treat leukemia. ..
  10. The role of inhibitory receptors in leukemia development
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    ..Moreover, the understanding of the ligand-receptor binding, the signaling events, and the downstream effectors in this newly identified pathway will directly guide the development of new therapeutic strategies for human AML. ..
    Daniel G Tenen; Fiscal Year: 2013
    ..As such, they are relevant to understanding the block in normal myeloid maturation from blasts to mature myeloid cells in AML. ..
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  13. Role of NF-kB in hematopoietic stem cells and leukemia-initiating cell formation
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  14. Zfx, A Novel Transcriptional Regulator of Hematopoiesis
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  15. Development of Inhibitors of the Leukemia Fusion Protein CBFbeta-SMMHC
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    ..These inhibitors also have the potential to be less toxic than standard chemotherapy, resulting in reduced side effects from treatment. ..
  16. MLL Function in the Maintenance of the Blood Forming System
    PATRICIA A ERNST; Fiscal Year: 2013
    ..abstract_text> ..