Grants and Contracts Details
Description
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.
Status | Finished |
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Effective start/end date | 6/1/11 → 2/28/14 |
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