The Role of the APC Tumor Suppressor Gene in Hematopoiesis and Leukemogenesis

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DESCRIPTION (provided by applicant): Emerging evidence suggests that cancers are derived from cancer-initiating cells that originate from normal stem cells or progenitors. However, the molecular basis by which a normal stem or progenitor cell is transformed into a cancer-initiating cell is still poorly understood. The myelodysplastic syndromes (MDS) are clonal disorders of hematopoietic stem cells (HSCs), characterized by ineffective hematopoiesis with a high rate of leukemic transformation. The APC tumor suppressor gene is involved in the development of colorectal carcinoma. A deletion of the long arm of chromosome 5 or loss of a whole chromosome 5, -5/del(5q), occurs at a high frequency in patients with primary MDS (10-15%) or therapy-related MDS (t-MDS) and therapy-related acute myeloid leukemia (t-AML) (40%). The APC gene is located on chromosome band 5q23, and is deleted >95% of patients with -5/del(5q), raising the question of whether APC acts as a tumor suppressor in the hematopoietic system. To examine the role of Apc in the function of HSCs and in normal hematopoiesis, we examined mice with a conditional Apc allele, and showed that inactivation of Apc in hematopoietic cells in vivo leads to rapid lethality due to bone marrow failure. In addition, loss of Apc results in enhanced cell cycle entry and increased apoptosis of HSCs and progenitor cells (HPCs), leading to rapid exhaustion of the HSC and HPC pool. These studies suggest that Apc is required for the function of HSCs and HPCs, and normal adult hematopoiesis. Additionally, in a pilot study, we showed that a cohort of mice with inactivation of a single allele of Apc in hematopoietic cells succumb to a severe anemia with macrocytosis, recapitulating several characteristic features of MDS and t-MDS with -5/del(5q). These features suggest that Apc haploinsufficient mice represent a novel and interesting disease model for MDS and t-MDS/t-AML with a -5/del(5q). We hypothesize that haploinsufficiency of APC contributes to the initiation and development of hematological malignancies through deregulation of the maintenance and the function of HSCs and HPCs. This hypothesis will be tested in three specific aims: (1) To determine whether haploinsufficiency of Apc contributes to the pathogenesis of hematological disorders via deregulation of the function of HSCs and myeloid progenitors; (2) To identify the genetic alterations that cooperate with haploinsufficiency of Apc in the transformation of HSCs into leukemia-initiating cells (LICs); and (3) To evaluate whether inhibition of the Wnt//2-catenin pathway prevents hematological disorders induced by inactivation of one or both alleles of Apc in vivo, and rescues the growth and differentiation defects of myeloid leukemia cells from t-MDS/t-AML patients with a -5/del(5q) ex vivo. The Apc haploinsufficient model provides us with a unique opportunity to study the molecular events that occur during the initiation of transformation of a normal stem or progenitor cell into a LIC, leading to the development of new effective therapeutic strategies targeting leukemia-initiating cells for MDS and t-MDS/t- AML with a -5/del(5q). PUBLIC HEALTH RELEVANCE: Myelodysplastic Syndrome (MDS), therapy-lated myelodysplastic syndrome (t-MDS) and acute myeloid leukemia (t-AML), are one subset of blood cancers. The APC tumor suppressor gene is deleted in >95% of MDS and t-MDS/t-AML patients with loss of chromosome 5 or deletion of chromosome 5q, and our preliminary data reveal that loss of a single allele of Apc leads to an MDS-like disease in our mouse model. In this proposal, we plan to determine how APC plays a role in the pathogenesis of MDS and t-MDS/t-AML, ultimately leading to new effective therapeutic strategies for these diseases.