In this issue of Blood Cancer Discovery, Stoddart and colleagues describe cooperative effects of exposing both the bone marrow microenvironment of recipient mice and donor hematopoietic stem and progenitor cells (HSPC) to an alkylating agent in a genetically accurate model of therapy-induced myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) characterized by chromosome 5q deletions. The authors further implicate senescence of alkylator-treated mesenchymal stem cells (MSC) as contributing to the microenvironmental damage and subsequent therapy-induced myeloid neoplasms (tMN). Loss of Trp53 function and somatic mutations in other DNA damage response (DDR) genes were associated with overt AML in this model. Together, these studies shed new light on the complex pathogenesis of tMN and establish a robust model for biologic and preclinical investigation. See related article by Stoddart et al., p. 32.

Bone marrow niches (endosteal and perivascular) play important roles in both normal bone marrow function and pathological processes such as cancer cell dormancy. Unraveling the mechanisms underlying these events in humans has been severely limited by models that cannot dissect dynamic events at the niche level. Utilizing microfluidic and stem cell technologies, we present a 3D in vitro model of human bone marrow that contains both the perivascular and endosteal niches, complete with dynamic, perfusable vascular networks. We demonstrate that our model can replicate in vivo bone marrow function, including maintenance and differentiation of CD34⁺ hematopoietic stem/progenitor cells, egress of neutrophils (CD66b⁺), and niche-specific responses to doxorubicin and granulocyte-colony stimulating factor. Our platform provides opportunities to accelerate current understanding of human bone marrow function and drug response with high spatial and temporal resolution.