Bone marrow microenvironment's role in hematopoietic neoplasms explored

The bone marrow, comprising over 20 cell types, tightly controls the balance between self-renewal, differentiation, dormancy, and proliferation of hematopoietic stem cells (HSCs). Clonal heterogeneity in hematological neoplasms, like AML and MDS, is characterized by chromosomal abnormalities and somatic mutations. These mutations affect RNA splicing, epigenetic machinery, cell signaling factors, and transcription factor genes, primarily in hematopoietic cells. Reports on the bone marrow microenvironment (BMME) as a primary disease driver are rare due to limited knowledge of its specific cell types. Recent single-cell technologies are mapping the 'bone marrow metropolis,' but its functional composition remains incompletely understood. The intricate network of regulatory mechanisms within this complex tissue is still under exploration. Mesenchymal stroma cells (MSCs) are recognized as key niche players supporting HSCs. A study showed that genetic modification of osteolineage cells in murine bone marrow disrupts hematopoietic system integrity. Targeted deletion of the miRNA-processing enzyme Dicer1 in osteoprogenitor cells impaired HSC survival, proliferation, and differentiation, resembling human MDS and progressing to leukemia. Another murine study reported that a mutated form of protein tyrosine phosphatase SHP2 in MSCs and osteoprogenitors drives myeloproliferative neoplasms (MPN). Ptpn11 mutations in BMME cells trigger excessive production of the CC chemokine CCL3, recruiting monocytes to HSC niches. This hyperactivates HSCs with interleukin-1β and other proinflammatory cytokines, exacerbating the MPN phenotype. Mice deficient for retinoic acid receptor γ (RARγ) in the BMME developed MPN-like disease. Increased β-catenin signaling and nuclear accumulation were reported in MDS/AML patient osteoblasts, with increased Notch signaling in hematopoietic cells. These findings support a niche-driven model of oncogenesis, where the initial event occurs in the stromal microenvironment, leading to secondary alterations in hematopoietic cells.