The p110 alpha and delta isoforms of PI3 kinase in hematopoiesis and leukemia


Principal Investigator: Kira Gritsman
Abstract: DESCRIPTION (provided by applicant): Acute myeloid leukemia (AML) affects 1 in 25,000 people per year, and is curable in only about 40% of cases. The mainstay of treatment is multi-agent chemotherapy and bone marrow transplantation, both of which have many complications and high mortality. This is largely attributed to the toxic effects that most antileukemic drugs have on hematopoietic stem cells (HSC), frequently leading to cytopenias. Therefore, it is crucial to determine which signaling pathways are important specifically in leukemic cells but not in HSCs, to enable the design of more specific and less toxic treatments for AML. The PI3 kinase (PI3K) pathway is pathologically activated in many human cancers, including AML. PI3K may also be important during hematopoiesis, as it is activated by hematopoietic growth factor receptors, such as erythropoietin receptor, c-kit receptor, and fms-like tyrosine kinase 3 (FLT3). In hematopoietic cells, receptor tyrosine kinases signal through the catalytic p110 subunit of PI3K, which has 3 isoforms (, , ), to activate the phosphorylation of the target kinase AKT. However, the roles of PI3K and its specific subunits in normal and leukemic stem cell function are poorly understood. We hypothesize that targeting individual subunits of PI3K may achieve the most selective anti-leukemic effect with minimal potential adverse affects. This proposal will utilize two novel genetic tools to investigate the roles of the PI3K subunits p110 and p110, individually and together, in leukemic cells and in normal HSCs: (1) mice with conditional deletion of p110 in hematopoietic cells and (2) double mutant mice with germline deletion of p110 and conditional deletion of p110. Preliminary data reveal that conditional deletion of p110 in HSCs results in impaired erythropoiesis, and slightly reduced HSC repopulating ability. As AKT signaling is maintained in p110-deleted bone marrow, we hypothesize that p110, a subunit expressed exclusively in hematopoietic cells, can complement for p110 in HSCs. In Specific Aim 1, we will analyze the effects of compound loss of p110 and p110 on HSC function and on AKT signaling in hematopoietic cells. Preliminary data suggests that deletion of p110 is insufficient to halt disease progression in at least some murine models of leukemia. Based on the failure of p110 excision to abrogate AKT signaling in hematopoietic cells, we hypothesize that it may be necessary to eliminate both p110 and p110 to inhibit the growth of leukemic cells. Specific Aim 2 will examine leukemia initiation and progression in mice after loss of p110, p110, or both using the bone marrow transplant system with retrovirally introduced mutated tyrosine kinases, including BCR-ABL, FLT3- ITD, and JAK2V617F. Specific Aim 3 will examine the roles of p110 and p110 in leukemic stem cell function in MLL-AF9-induced leukemia, which has been particularly difficult to target therapeutically. Together, these studies will provide important insights into the role and mechanism of PI3K signal transduction in HSCs, and the best strategies for therapeutic targeting of this pathway in leukemia. PUBLIC HEALTH RELEVANCE: PI3 kinase signaling is of central importance in solid tumors, but its roles in normal and leukemic stem cell function are poorly understood. This proposal will use mouse knockout models to examine whether the p110 and p110 subunits of PI3 kinase are important for normal HSC function and are feasible targets for leukemia therapy.
Funding Period: 2010-09-15 - 2015-08-31
more information: NIH RePORT

Detail Information

Research Grants30

  1. The role of Jmjd1c in normal and leukemic hematopoiesis
    Nan Zhu; Fiscal Year: 2013
    ..Scott Armstrong, recognized leader in leukemia field. Dr. Armstrong has proposed a career- development plan to further Dr. Zhu's scientific development and to help her transition to independence. ..
  2. H3K79 Methylation in Hematopoietic Stem Cell Development and MLL-Rearranged Leuk
    Kathrin M Bernt; Fiscal Year: 2013
    ..Stuart Schreiber. Execution of these aims will elucidate fundamental mechanisms of chromatin regulation in benign and malignant hematopoiesis. ..
  3. Functional and Molecular Dissection of Myeloproliferative Neoplasm Stem Cells
    Ann Mullally; Fiscal Year: 2013
    ..Finally, the candidate has recruited Dr. Ross Levine, one of the initial scientific investigators to describe the JAK2V617F mutation in MPN, as a collaborator for her project. ..
  4. DF/HCC Kidney Cancer SPORE
    David McDermott; Fiscal Year: 2013
    ..The overall goal of the DF/HCC Kidney Cancer SPORE is the translation of biological and technological advances into clinically meaningful advances for patients with kidney cancer. ..
  5. Targeting Leukemia Stem Cells with Dietary Selenium
    KUMBLE SANDEEP PRABHU; Fiscal Year: 2013
  6. Experimental Therapeutics of Leukemia
    John C Byrd; Fiscal Year: 2013
    ..We believe that this SPORE group, as a multidisciplinary, highly interactive and accomplished team, will have a substantial impact on improving the clinical outcome of leukemia patients. ..
  7. Epidemiology of Breast Cancer Subtypes in African American Women: a Consortium
    Julie R Palmer; Fiscal Year: 2013
    ..By pooling our data, specimens, and importantly, expertise to investigate these synergist hypotheses, we will elucidate much of the etiology of aggressive, early onset breast cancers in AA women. ..
  8. Hypoxia-Selective Kinase Inhibitors for Leukemia Therapy
    Marina Y Konopleva; Fiscal Year: 2013
    ..If successful, this approach will provide mechanism-based rationale for eliminating leukemic cells within the hypoxic BM niches and improve cure rates in AML. ..
  9. Role of Setbp1 in leukemic stem cell self-renewal
    Yang Du; Fiscal Year: 2013
    ..Our study will also test whether targeting LSC self-renewal is efficient in treating CML blast crisis for which no effective treatments are currently available. ..
  10. Mechanisms of State Switching in Sleep and Sleep Apnea
    Clifford B Saper; Fiscal Year: 2013
    ..This work will help to design interventions for improving the health of patients with OSA. ..
  11. Zfx, A Novel Transcriptional Regulator of Hematopoiesis
    Boris Reizis; Fiscal Year: 2013
    ..We have identified a novel gene, Zfx, which appears important for leukemia development and propagation. Studies on the role and mechanism of action of Zfx in leukemia may provide novel therapeutic approaches to the disease. ..
  12. Role of DOK family proteins in lung tumor suppression
    Pier Paolo Pandolfi; Fiscal Year: 2013
    ..This work could identify additional targets for the prevention and treatment of human lung cancer and discover genetic criteria that determine tumor phenotype, progression, and response to therapy. ..
    Daniel C Link; Fiscal Year: 2013
    ..We believe this research will lead to novel strategies to specifically target the leukemic stem cell and ultimately lead to improved cure rates in individuals with leukemia. ..
  14. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
    ..The insights gained from the data generated from these studies will provide novel molecular targets for the development of new therapeutic strategies to treat patients with lung injury. ..
    Michal Laniado Schwartzman; Fiscal Year: 2013
    ..ular tone, in the pathophysiology of hypertension and cardiovascular disease. ..
    DAVID MORSE LIVINGSTON; Fiscal Year: 2013
    ..The goal of this Program is to continue to shed new light on cellular transformation events that also underpin human cancer development and generate insights that lead to new cancer therapeutic strategies. ..
  17. Normal &Neoplastic Growth in the Brain
    Suzanne J Baker; Fiscal Year: 2013
    ..Integrated analyses within the group will identify common and unique signal transduction pathways in pediatric brain tumorigenesis. ..
  18. Role of 11q23 Chromosome Abnormalities in the Causation of Acute Leukemia
    Carlo M Croce; Fiscal Year: 2013
    ..abstract_text> ..
  19. Discovering chemical tools for acute myelogenous leukemia
    JING RUEY JOANNA YEH; Fiscal Year: 2013
  20. Cell signaling as a leukemia biomarker
  21. Mechanistic Pharmacology of Anti-Mitotics and Apoptosis Regulation
    Timothy J Mitchison; Fiscal Year: 2013
    ..In aim 4 we will pursue several approaches towards translating mechanistic understanding from aims 1-3 into improved patient care. ..
  22. Role of NF-kB in hematopoietic stem cells and leukemia-initiating cell formation
    Christopher A Klug; Fiscal Year: 2013
    ..This proposal will examine the role of NF-?B in normal hematopoietic stem/progenitor cell function and test whether activation of NF-?B is sufficient to initiate and/or maintain LIC activity in AML. ..