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Author(s): Bo Shen [sup.1] , Alpaslan Tasdogan [sup.1] , Jessalyn M. Ubellacker [sup.1] , Jingzhu Zhang [sup.1] , Elena D. Nosyreva [sup.2] , Liming Du [sup.1] , Malea M. Murphy [...], Stromal cells in adult bone marrow that express leptin receptor (LEPR) are a critical source of growth factors, including stem cell factor (SCF), for the maintenance of haematopoietic stem cells and early restricted progenitors.sup.1-6. LEPR.sup.+ cells are heterogeneous, including skeletal stem cells and osteogenic and adipogenic progenitors.sup.7-12, although few markers have been available to distinguish these subsets or to compare their functions. Here we show that expression of an osteogenic growth factor, osteolectin.sup.13,14, distinguishes peri-arteriolar LEPR.sup.+ cells poised to undergo osteogenesis from peri-sinusoidal LEPR.sup.+ cells poised to undergo adipogenesis (but retaining osteogenic potential). Peri-arteriolar LEPR.sup.+osteolectin.sup.+ cells are rapidly dividing, short-lived osteogenic progenitors that increase in number after fracture and are depleted during ageing. Deletion of Scf from adult osteolectin.sup.+ cells did not affect the maintenance of haematopoietic stem cells or most restricted progenitors but depleted common lymphoid progenitors, impairing lymphopoiesis, bacterial clearance, and survival after acute bacterial infection. Peri-arteriolar osteolectin.sup.+ cell maintenance required mechanical stimulation. Voluntary running increased, whereas hindlimb unloading decreased, the frequencies of peri-arteriolar osteolectin.sup.+ cells and common lymphoid progenitors. Deletion of the mechanosensitive ion channel PIEZO1 from osteolectin.sup.+ cells depleted osteolectin.sup.+ cells and common lymphoid progenitors. These results show that a peri-arteriolar niche for osteogenesis and lymphopoiesis in bone marrow is maintained by mechanical stimulation and depleted during ageing. A peri-arteriolar niche in the bone marrow for osteogenesis and lymphopoiesis is maintained by mechanical stimulation and is depleted during ageing.

SWI/SNF chromatin remodelers play critical roles in development and cancer. The causal links between SWI/SNF complex disassembly and carcinogenesis are obscured by redundancy between paralogous components. Canonical cBAF-specific paralogs ARID1A and ARID1B are synthetic lethal in some contexts, but simultaneous mutations in both ARID1s are prevalent in cancer. To understand if and how cBAF abrogation causes cancer, we examined the physiologic and biochemical consequences of ARID1A/ARID1B loss. In double knockout liver and skin, aggressive carcinogenesis followed de-differentiation and hyperproliferation. In double mutant endometrial cancer, add-back of either induced senescence. Biochemically, residual cBAF subcomplexes resulting from loss of ARID1 scaffolding were unexpectedly found to disrupt polybromo containing pBAF function. 37 of 69 mutations in the conserved scaffolding domains of ARID1 proteins observed in human cancer caused complex disassembly, partially explaining their mutation spectra. ARID1-less, cBAF-less states promote carcinogenesis across tissues, and suggest caution against paralog-directed therapies for ARID1-mutant cancer., Competing Interests: Competing Interests Statement At the time of publication, Hao Zhu owned Ionis Pharmaceuticals stock worth less than $10,000. Hao Zhu has active collaborations with Alnylam Pharmaceuticals and Twenty-Eight Seven Therapeutics. The remaining authors disclose no conflicts.