Abnormality in Bone Marrow Stromal Cell Subpopulations as a possible Contributor to the Initiation and Progression of Acute Myeloid Leukemia

Background: Hematopoietic stem cells reside in the bone marrow (BM) in specialized microenvironment containing diverse stromal cell subpopulations, mainly adipocytes and osteocytes that co-exist in a controlled balance maintaining normal hematopoiesis. In hematological malignancies, such as acute myeloid leukemia (AML), multiple factors may operate to create dysfunctional BM niche. Whether the primary impairment occurs within the niche itself or results from its interaction with leukemia-initiating cells is yet to be determined. These processes can combine to generate an abnormal milieu supporting AML initiation/propagation.

Hypothesis/aims: Imbalance between niche subpopulations could result in the development of leukemic stem cells/pre-leukemic cells, leading to leukemia full blown. The current study aimed at characterizing the composition of AML BM niche subpopulations and evaluate the ability of these subpopulations to support AML cell viability.

Methods: BM samples of 10 AML patients and 13 healthy donors were used for genetic, immuno-phenotypic and functional analyses using exome sequencing, FACS analysis, ELISA and CFU assays, respectively.

Results: We found significantly a reduced FABP4 and Osteocalcin secretion in AML BM plasma as compared to healthy controls. Mesenchymal stem cell differentiation potential toward adipocytes and osteocytes were altered in AML versus healthy donors. Specifically, we could show alteration in the adipogenesis potential. Adipocytes from AML showed reduced support in AML CFU formation. Mutation in AHNAK2 gene was found in AML stromal cells in our study.

Conclusions: These findings support the presence of abnormal composition of adipocytes and osteocytes in AML patients and the possibility of stromal cells contribution in leukomogenesis