Aging is associated with significant changes in the hematopoietic system, including increased inflammation, impaired hematopoietic stem cell (HSC) function, and increased incidence of myeloid malignancy. Inflammation of aging (“inflammaging”) has been proposed as a driver of age-related changes in HSC function and myeloid malignancy, but mechanisms linking these phenomena remain poorly defined. We identified loss of miR-146a as driving aging-associated inflammation in AML patients. miR-146a expression declined in old wild-type mice, and loss of miR-146a promoted premature HSC aging and inflammation in young miR-146a–null mice, preceding development of aging-associated myeloid malignancy. Using single-cell assays of HSC quiescence, stemness, differentiation potential, and epigenetic state to probe HSC function and population structure, we found that loss of miR-146a depleted a subpopulation of primitive, quiescent HSCs. DNA methylation and transcriptome profiling implicated NF-κB, IL6, and TNF as potential drivers of HSC dysfunction, activating an inflammatory signaling relay promoting IL6 and TNF secretion from mature miR-146a−/− myeloid and lymphoid cells. Reducing inflammation by targeting Il6 or Tnf was sufficient to restore single-cell measures of miR-146a−/− HSC function and subpopulation structure and reduced the incidence of hematological malignancy in miR-146a−/− mice. miR-146a−/− HSCs exhibited enhanced sensitivity to IL6 stimulation, indicating that loss of miR-146a affects HSC function via both cell-extrinsic inflammatory signals and increased cell-intrinsic sensitivity to inflammation. Thus, loss of miR-146a regulates cell-extrinsic and -intrinsic mechanisms linking HSC inflammaging to the development of myeloid malignancy.

Inflammation is associated with bone marrow failure syndromes, but how specific molecules impact the bone marrow microenvironment is not well elucidated. We report a novel role for the miR-145 target, Toll/interleukin-1 receptor domain containing adaptor protein (TIRAP), in driving bone marrow failure. We show that TIRAP is overexpressed in various types of myelodysplastic syndromes (MDS) and suppresses all three major hematopoietic lineages. TIRAP expression promotes up-regulation of Ifnγ, leading to myelosuppression through Ifnγ-Ifnγr–mediated release of the alarmin, Hmgb1, which disrupts the bone marrow endothelial niche. Deletion of Ifnγ blocks Hmgb1 release and is sufficient to reverse the endothelial defect and restore myelopoiesis. Contrary to current dogma, TIRAP-activated Ifnγ-driven bone marrow suppression is independent of T cell function or pyroptosis. In the absence of Ifnγ, TIRAP drives myeloproliferation, implicating Ifnγ in suppressing the transformation of MDS to acute leukemia. These findings reveal novel, noncanonical roles of TIRAP, Hmgb1, and Ifnγ in the bone marrow microenvironment and provide insight into the pathophysiology of preleukemic syndromes.

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Activation of inflammatory pathways is associated with bone marrow failure syndromes, but how specific molecules impact on the marrow microenvironment is not well elucidated. We report a novel role for the miR-145 target, Toll/Interleukin-1 receptor domain containing adaptor protein (TIRAP), in driving bone marrow failure. We show that TIRAP is overexpressed in various types of myelodysplastic syndromes (MDS), and suppresses all three major hematopoietic lineages.. Constitutive expression of TIRAP in hematopoietic stem/progenitor cells (HSPC) promotes upregulation of Ifnγ, leading to bone marrow failure. Myelopoiesis is suppressed through Ifnγ-Ifnγr-mediated release of the alarmin, Hmgb1, which disrupts the marrow endothelial niche. Deletion of Ifnγ or Ifnγr blocks Hmgb1 release and is sufficient to reverse the endothelial defect and prevent myelosuppression. In contrast, megakaryocyte and erythroid production is repressed independently of the Ifnγ receptor. Contrary to current dogma, TIRAP-activated Ifnγ-driven marrow suppression is independent of T cell function or pyroptosis.In the absence of Ifnγ, TIRAP drives myeloproliferation, implicating Ifnγ in suppressing the transformation of bone marrow failure syndromes to myeloid malignancy. These findings reveal novel, non-canonical roles of TIRAP, Hmgb1 and Ifnγ function in the marrow microenvironment,and provide insight into the pathophysiology of preleukemic syndromes.AGGGTCTACGGGGCAATTT; rev-ACAGTCCGTTTCCGGAGTT); mFasL (for-TTTAACAGGGAACCCCCACT; rev-GATCACAAGGCCACCTTTCT); mIfna (for-GACTTTGGATTCCCGCAGGAGAAG; rev-CTGCATCAGACAGCCTTGCAGGTC); mIfnab (for-CCTGCTGGCTGTGAGGAAAT; rev-CTCACTCAGACTTGCCAGCA); mHmgb1 (for-GTTCTGAGTACCGCCCCAAA; rev-GTAGGCAGCAATATcCTTCTC); mIL-4 (for-TTGAACGAGGTCACAGGAGA; rev-AAATATGCGAAGCACCTTGG); mIL-17a (for-CGCAAAAGTGAGCTCCAGA; rev-TGAGCTTCCCAGATCACAGA); mIL-1rn (for-GTGAGACGTTGGAAGGCAGT; rev-GCATCTTGCAGGGTCTTTTC); mTNFSF11 (for-GACTCCATGAAAACGCAGGT; rev-CCCACAATGTGTTGCAGTTC); mIL-13 (for-TGTGTCTCTCCCTCTGACCC; rev-CACACTCCATACCATGCTGC); mIL-1a (for-AGCGCTCAAGGAGAAGACC; rev-CCAGAAGAAAATGAGGTCGG); mIL-27 (for-GTGACAGGAGACCTTGGCTG; rev-AGCTCTTGAAGGCTCAGGG); mCSF1 (for-CCAGGATGAGGACAGACAGG; rev-GGTAGTGGTGGATGTTCCCA); mCCL2 (for-AGGTCCCTGTCATGCTTCTG; rev-GGGATCATCTTGCTGGTGAA); mIL-23a (for-TTGTGACCCACAAGGACTCA; rev-AGGCTCCCCTTTGAAGATGT); mIfna13 (for-CTTTGGATTCCCACAGGAGA; rev-TTCCATGCAGCAGATGAGTC); mIfna2 (for-GCAGATCCAGAAGGCTCAAG; rev-GGTGGAGGTCATTGCAGAAT); mGAPDH (for-TGCAGTGGCAAAGTGGAGAT; rev-TTTGCCGTGAGGAGTCATA); hIFNγR1 (for-CCAGGGTTGGACAAAAAGAA; rev-CGGGATCATAATCGACTTCC); hIFNγR2 (for-TGACAATGCCTTGGTTTCAA; rev-ATCAGCGATGTCAAAGGGAG); mCamp (for-GCTGTGGCGGTCACTATCAC; rev-TGTCTAGGGACTGCTGGTTGA); mTmsb10 (for-CCGGACATGGGGGAAATCG; rev-CCTGTTCAATGGTCTCTTTGGTC); mTmsb4x (for-ATGTCTGACAAACCCGATATGGC; rev-CCAGCTTGCTTCTCTTGTTCA); mAnxa6 (for-

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