Role of MicroRNA-146a in normal and malignant hematopoietic stem cell function

Regulation of hematopoiesis is controlled by microRNAs (miRNAs). In this review, we focus on miR-146a, and its role in regulating normal and malignant hematopoiesis. miR-146a is a negative regulator of immune cell activation by repressing two targets, TRAF6 and IRAK1. Genetic deletion of miR-146a confirmed a role of miR-146a during innate immune signaling as well as for hematopoietic stem cell function. miR-146a is also implicated in the pathogenesis of human myelodysplastic syndromes (MDSs) as it is located within a commonly deleted region on chromosome 5, and miR-146a-deficient mice exhibit features of an MDS-like disease. With new insight into miR-146a through genetic and expression analyses, we highlight and discuss the recent advances in the understanding of miR-146a in physiological hematopoiesis during steady-state and inflammation, as well as in MDS

Chemotherapy resistance in acute myeloid leukemia is mediated by A20 suppression of spontaneous necroptosis

Acute myeloid leukemia (AML) is a deadly hematopoietic malignancy. Although many patients achieve complete remission with standard induction therapy, a combination of cytarabine and anthracycline, ~40% of patients have induction failure. These refractory patients pose a treatment challenge, as they do not respond to salvage therapy or allogeneic stem cell transplant. Herein, we show that AML patients who experience induction failure have elevated expression of the NF-κB target gene tumor necrosis factor alpha-induced protein-3 (TNFAIP3/A20) and impaired necroptotic cell death. A20High AML are resistant to anthracyclines, while A20Low AML are sensitive. Loss of A20 in AML restores sensitivity to anthracycline treatment by inducing necroptosis. Moreover, A20 prevents necroptosis in AML by targeting the necroptosis effector RIPK1, and anthracycline-induced necroptosis is abrogated in A20High AML. These findings suggest that NF-κB-driven A20 overexpression plays a role in failed chemotherapy induction and highlights the potential of targeting an alternative cell death pathway in AML

Germline DDX41 mutations cause ineffective hematopoiesis and myelodysplasia

DDX41 mutations are the most common germline alterations in adult myelodysplastic syndromes (MDSs). The majority of affected individuals harbor germline monoallelic frameshift DDX41 mutations and subsequently acquire somatic mutations in their other DDX41 allele, typically missense R525H. Hematopoietic progenitor cells (HPCs) with biallelic frameshift and R525H mutations undergo cell cycle arrest and apoptosis, causing bone marrow failure in mice. Mechanistically, DDX41 is essential for small nucleolar RNA (snoRNA) processing, ribosome assembly, and protein synthesis. Although monoallelic DDX41 mutations do not affect hematopoiesis in young mice, a subset of aged mice develops features of MDS. Biallelic mutations in DDX41 are observed at a low frequency in non-dominant hematopoietic stem cell clones in bone marrow (BM) from individuals with MDS. Mice chimeric for monoallelic DDX41 mutant BM cells and a minor population of biallelic mutant BM cells develop hematopoietic defects at a younger age, suggesting that biallelic DDX41 mutant cells are disease modifying in the context of monoallelic DDX41 mutant BM

Inactivation of p53 provides a competitive advantage to del(5q) myelodysplastic syndrome hematopoietic stem cells during inflammation

Inflammation is associated with the pathogenesis of myelodysplastic syndromes (MDS) and emerging evidence suggests that MDS hematopoietic stem and progenitor cells (HSPC) exhibit an altered response to inflammation. Deletion of chromosome 5 (del(5q)) is the most common chromosomal abnormality in MDS. Although this MDS subtype contains several haploinsufficient genes that impact innate immune signaling, the effects of inflammation on del(5q) MDS HSPC remains undefined. Utilizing a model of del(5q)-like MDS, inhibiting the IRAK1/4-TRAF6 axis improved cytopenias, suggesting that activation of innate immune pathways contributes to certain clinical features underlying the pathogenesis of low-risk MDS. However, low-grade inflammation in the del(5q)-like MDS model did not contribute to more severe disease but instead impaired the del(5q)-like HSPC as indicated by their diminished numbers, premature attrition and increased p53 expression. Del(5q)-like HSPC exposed to inflammation became less quiescent, but without affecting cell viability. Unexpectedly, the reduced cellular quiescence of del(5q) HSPC exposed to inflammation was restored by p53 deletion. These findings uncovered that inflammation confers a competitive advantage of functionally defective del(5q) HSPC upon loss of p53. Since TP53 mutations are enriched in del(5q) AML following an MDS diagnosis, increased p53 activation in del(5q) MDS HSPC due to inflammation may create a selective pressure for genetic inactivation of p53 or expansion of a pre-existing TP53-mutant clone

Chronic Innate Immune Signaling in Myelodysplasia

Abstract Chronic inflammatory diseases associated with activated innate immune signaling pathways often precede Myelodysplastic Syndromes (MDS), thus a role for chronic innate immune signaling in hematopoietic cells is suspected in the development of MDS. The innate immune system recognizes pathogens and host cellular by-products by pattern recognition receptors (PRR). Among the first PRRs to be identified were the Toll-like receptors (TLRs), which consist of 10 human members. Upon binding to ligand, TLRs recruit intracellular adaptors, kinases, and effector molecules which results in pathway activation. Chronic TLR signaling impairs HSC function, creates an inflammatory environment, and alters normal hematopoiesis, which suggests a causal role in MDS. Despite growing evidence linking dysregulation of innate immune signaling in MDS, how sustained activation of innate immune signaling downstream of various receptor families contributes to MDS remains an open question. This talk will highlight the recent evidence that implicates a cell-intrinsic role of innate immune pathway activation in MDS HSC and environmental inflammatory factors that are involved in the pathogenesis of MDS. Disclosures No relevant conflicts of interest to declare. </jats:sec