Research Project
10210269
PROJECT SUMMARY/ABSTRACT Expansion and progressive displacement of hematopoietic stem/progenitor cells (HSPCs) from the bone marrow to peripheral blood observed in primary myelofibrosis (PMF) suggests that aberrant communication between stem cells and the bone marrow microenvironment (BMME) is key to understanding the etiology of this disease. Molecular mechanisms that contribute to PMF pathology at the stem cell level are not known. JAK/STAT cascade was found to be dysregulated in most PMF cases and in nearly all myeloproliferative neoplasms (MPNs). However, the extent to which currently available inhibitors that target JAK/STAT pathway alter the underlying disease and affect malignant hematopoietic stem cells is not clear. Our long term goal is to better understand the molecular processes that control abnormal interactions between malignant HSPCs and their BMME, and identify new targets for pharmacological intervention in PMF and other MPNs. The overall objective of this application is to identify new signaling mechanisms involved in the initiation of age- induced myelofibrosis and related MPNs. Our recent findings indicate that (1) conditional deletion of the gene encoding the Abelson interactor-1 (Abi-1) adapter protein in mouse bone marrow induces myelofibrotic phenotype, (2) hematopoietic progenitors and granulocytes from patients with PMF show decreased Abi-1 protein and transcript levels, (3) loss of Abi-1 positively affects activity of Src Family Kinases (SFKs) and their downstream signaling to STAT3 and NFkB, and finally (4) loss of Abi-1 in malignant HSPCs leads to dysregulation of adhesion and quiescence and induces their chemoresistance. Our central hypothesis is that loss of Abi-1, through a positive effect on SFKs signaling and its downstream cross-talk with STAT3 and NFkB, is a factor that initiates fibrosis-inducing changes at the malignant stem cell level. Our central hypothesis will be tested in the following three Specific Aims. In Specific Aim 1 we will use our established Abi-1 conditional bone marrow-specific mouse model (Abi-1 BM KO) to assess the effect of Abi-1 loss on the communication between HSPCs and BMME and its role in the development of age-related myelofibrosis. In Specific Aim 2, we will use advanced microscopy and biochemical arrays to elucidate the mechanism by which Abi-1 directly controls SFKs and their downstream signaling to STAT3 and NF?B. In Specific Aim 3 using Abi-1 BM KO we will evaluate the effects of SFKs inhibition on Abi-1-loss-induced myelofibrosis. Completion of these aims will elucidate Abi-1-driven mechanisms that lead to the development of marrow fibrosis induced by malignant stem cells in MPNs, and uncover potential new therapeutic approaches that directly address their pathogenesis. Our strategy utilizes newly established animal models and has the potential to significantly advance the understanding of tumor and stromal cell interactions. This knowledge will contribute to an emerging conceptual shift in the field from a focus on cancer cells to a broader and more complex understanding of cancer as a systemic disease existing in a microenvironmental context.
