Bone marrow neuropathy in acute myeloid leukemia
By
Aurora Bernal
Postdoctoral researcher
Stem Cell Aging and Cancer Research Group, IMB
Acute myeloid leukemia (AML) is an aggressive and heterogeneous group of hematological malignancies characterized by aberrant myeloid cell proliferation and differentiation. The bone marrow (BM) stem cell niche that tightly controls the function of hematopoietic stem cells and progenitors (HSPC) may contribute to this heterogeneity. BM nestin+ cells innervated by sympathetic nerves are components of the stem cell niche and regulate normal HSPC function. Further, our recent work demonstrates how damage to this regulatory circuit is essential for development of myeloproliferative neoplasms, while its rescue/compensation shows therapeutic potential. Our aim now is to study the role of the regulatory circuit exerted by nerve fibers and nestin+ cells to drive AML.
To address this question we are using a genetically engineered mouse model that expresses the human NRASG12D oncogene in an inducible way in blood cells. Although NRASG12D is a frequent mutation in human AML, its expression in mouse models promotes a mild and chronic disease, but it allows stepwise analysis of AML development.
So far, we have been able to show neuropathy of the BM niche in AML that is concomitant with reduction of nestin+ cells at early stages of disease. To understand the pathogenic role of these changes, enforced sympathectomy was performed and resulted in expansion of c-Kit+ progenitors in leukemic mice. On-going and future work to provide insights into these events will be presented. Our plan is to test the neural component of the BM niche as a therapeutic target for AML.
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