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

Myeloid Malignancies with Chromosome 5q Deletions Acquire a Dependency on an Intrachromosomal NF-κB Gene Network

SummaryChromosome 5q deletions (del[5q]) are common in high-risk (HR) myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML); however, the gene regulatory networks that sustain these aggressive diseases are unknown. Reduced miR-146a expression in del(5q) HR MDS/AML and miR-146a−/− hematopoietic stem/progenitor cells (HSPCs) results in TRAF6/NF-κB activation. Increased survival and proliferation of HSPCs from miR-146alow HR MDS/AML is sustained by a neighboring haploid gene, SQSTM1 (p62), expressed from the intact 5q allele. Overexpression of p62 from the intact allele occurs through NF-κB-dependent feedforward signaling mediated by miR-146a deficiency. p62 is necessary for TRAF6-mediated NF-κB signaling, as disrupting the p62-TRAF6 signaling complex results in cell-cycle arrest and apoptosis of MDS/AML cells. Thus, del(5q) HR MDS/AML employs an intrachromosomal gene network involving loss of miR-146a and haploid overexpression of p62 via NF-κB to sustain TRAF6/NF-κB signaling for cell survival and proliferation. Interfering with the p62-TRAF6 signaling complex represents a therapeutic option in miR-146a-deficient and aggressive del(5q) MDS/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

Innate immune pathways and inflammation in hematopoietic aging, clonal hematopoiesis, and MDS.

With a growing aged population, there is an imminent need to develop new therapeutic strategies to ameliorate disorders of hematopoietic aging, including clonal hematopoiesis and myelodysplastic syndrome (MDS). Cell-intrinsic dysregulation of innate immune- and inflammatory-related pathways as well as systemic inflammation have been implicated in hematopoietic defects associated with aging, clonal hematopoiesis, and MDS. Here, we review and discuss the role of dysregulated innate immune and inflammatory signaling that contribute to the competitive advantage and clonal dominance of preleukemic and MDS-derived hematopoietic cells. We also propose how emerging concepts will further reveal critical biology and novel therapeutic opportunities

Nuclear deubiquitination in the spotlight : the multifaceted nature of USP7 biology in disease

Ubiquitination is a versatile and tightly regulated post-translational protein modification with many distinct outcomes affecting protein stability, localization, interactions, and activity. Ubiquitin chain linkages anchored on substrates can be further modified by additional post-translational modifications, including phosphorylation and SUMOylation. Deubiquitinases (DUBs) reverse these ubiquitin marks with matched levels of precision. Over hundred known DUBs regulate a wide variety of cellular events. In this review, we focus on ubiquitin-specific protease 7 (USP7, also known as herpesvirus-associated ubiquitin-specific protease, or HAUSP) as one of the best studied, disease-associated DUBs. By highlighting the functions of USP7, particularly in the nucleus, and the emergence of the newest generation of USP7 inhibitors, we illustrate the importance of individual DUBs in the nucleus, and the therapeutic prospects of DUB targeting in human disease

Mouse gene targeting reveals an essential role of mTOR in hematopoietic stem cell engraftment and hematopoiesis

mTOR integrates signals from nutrients and growth factors to control protein synthesis, cell growth, and survival. Although mTOR has been established as a therapeutic target in hematologic malignancies, its physiological role in regulating hematopoiesis remains unclear. Here we show that conditional gene targeting of mTOR causes bone marrow failure and defects in multi-lineage hematopoiesis including myelopoiesis, erythropoiesis, thrombopoiesis, and lymphopoiesis. mTOR deficiency results in loss of quiescence of hematopoietic stem cells, leading to a transient increase but long-term exhaustion and defective engraftment of hematopoietic stem cells in lethally irradiated recipient mice. Furthermore, ablation of mTOR causes increased apoptosis in lineage-committed blood cells but not hematopoietic stem cells, indicating a differentiation stage-specific function. These results demonstrate that mTOR is essential for hematopoietic stem cell engraftment and multi-lineage hematopoiesis