Deconstructing Niche Contributions to Bone Marrow Failure and Leukemogenesis in Shwachman-Diamond Syndrome

Myeloid malignancies are driven by (epi)genetic aberrations in hematopoietic stem and/or progenitor cells (HSPC). HSPC in these disorders typically acquire a number of genetic lesions that, in concert, drive malignant transformation. How a single HSC, generally considered to be in a predominantly quiescent state in the postnatal bone marrow under homeostatic conditions, acquires multiple mutations, remains incompletely understood. Another central question remains how a mutated cell or 'preleukemic clone' persists and sometimes gains competitive advantage over non-mutated HSPC, while not always explained by hematopoietic cell-intrinsic capacities caused by the mutated state.

Evolution principles predict that a cell's direct environment, or HSPC niche, may play critical roles in the induction and selection of genetic clones within a population. In earlier work, we postulated a concept of niche-induced oncogenesis in the hematopoietic system, wherein primary alterations in the mesenchymal stem cell niche can drive malignant transformation of supported, but distinct HSPC.

Other emerging data support the idea of 'niche-facilitated' leukemogenesis, in which primary alterations in hematopoietic cells drive changes in their mesenchymal niche, facilitating leukemic evolution. Elucidation of the molecular signaling underlying these concepts holds great promise for novel avenues to attenuate leukemic evolution in preleukemic syndromes.

Congenital, monogenic, bone marrow failure syndromes with leukemia predisposition, in which mutations in a single gene, present in both HSPC and niche cells, drives tissue failure, clonal evolution and malignant transformation, provide an unprecedented model system to study the molecular mechanisms and human relevance of these concepts.

The lecture will address the findings of studies in Shwachman-Diamond Syndrome (SDS), caused by constitutive, bi-allelic, loss-of-function, mutations in the ribosome biogenesis gene SBDS, and characterized by bone abnormalities, neutropenia and a striking propensity to develop MDS/AML.

Mouse models of global Sbds deficiency ('full knockouts') are embryonically lethal. In order to investigate the contributions of hematopoietic and niche cells to neutropenia and leukemogenesis, a 'deconstructing' approach, targeting deletion of Sbds to specific cell types in the bone marrow environment, needs to be taken. Targeted downregulation of Sbds in Cebpa -expressing HSPC and their downstream progeny results in profound neutropenia, caused by impaired lineage progression specifically at the myelocyte phase of myeloid development and associated with activation of the Tp53 tumor suppressor pathway. Myelodysplasia and leukemia, however, were not observed, suggesting that hematopoietic cell-non-autonomous processes may contribute to these processes in SDS. Mesenchymal-specific deletion of Sbds (Osterix -cre Sbds^fl/fl ) faithfully recapitulated both skeletal and myelodysplastic characteristics of human disease. The Sbds -deficient mesenchymal niche induces genotoxic stress in HSPC. Mechanistically, transcriptional activation of an inflammatory signature in niche cells, downstream of Tp53 activation, is implicated. Transcriptional activation of this signaling axis in the mesenchymal niche was found in a subset of MDS patients to predict leukemic evolution. The data support the idea that mesenchymal niche cells make a necessary contribution to disease pathogenesis in SDS.

The findings complement emerging data from mouse models of niche-facilitated oncogenesis and human disease, pointing at inflammatory signaling in HSPC niches as a biologic commonality in preleukemia and myeloid neoplasm. A hypothetical model can be proposed of 'mesenchymal niche inflammation' promoting bone marrow failure, genotoxic stress, genetic instability and clonal evolution, of broader relevance to congenital bone marrow failure and leukemia predisposition syndromes. Recent data as well as controversies and uncertainties concerning this evolving new paradigm will be discussed.