Grants and Contracts Details
The long-term goal of the proposed research project is to unravel the molecular pathogenesis of myeloproliferative neoplasms (MPNs) and to develop more effective treatments for patients with these disorders. The MPNs are clonal hematopoietic malignancies characterized by overproduction of blood cells1.The disease originates from hematopoietic (blood-forming) stem cells (HSCs) that are transformed by multiple chromosomal lesions2,3. For example, BCR-ABL (the product of Philadelphia chromosome translocation) and a somatic point mutation (V617F) in the Janus Kinase 2 (JAK2) are mutants found in the majority of MPN patients4,5. Therapeutic strategies targeting these genetic events have been used to treat patients6-8. However it has become evident that the cure is difficult to achieve as a consequence of the complicated, yet largely unknown, molecular mechanisms leading to the transformation of HSCs9. It is imperative to advance our knowledge of molecular mechanisms underlying these disorders and to translate scientific discoveries into more effective treatment to MPN patients. Here, I propose to investigate the role of a novel HSC regulatory gene, latexin (Lxn), in tumorigenesis of MPNs. I previously discovered that Lxn is a negative regulator of HSC numbers and controls blood cell production10. In Lxn knock-out mouse model, I found that loss of Lxn resulted in an increase in the number of white blood cells (leukocytosis), particularly myeloid cells, in the peripheral blood, enlarged spleen (splenomegaly), and an aberrant accumulation of hematopoietic stem and progenitors cells (HSPCs) in the bone marrow. Notably, this Lxn knock-out phenotype recapitulates essential characteristics of human MPNs. I also found that Lxn expression was absent or significantly reduced in HSPCs from blood and marrow of patients with leukemia and lymphomas. I thus hypothesize that Lxn functions as a tumor suppressor and its dysregulation contributes to the malignant transformation of HSCs and pathogenesis of MPNs.
|Effective start/end date||6/1/11 → 10/31/14|
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