During many years, very limited data had been available on specific gene mutations in MDS in particular due to the fact that balanced chromosomal translocations (which have allowed to discover many ...“leukemia” genes) are very rare in MDS, while chromosomal deletions are generally very large, making it difficult to identify genes of interest. Recently, the advent of next generation sequencing (NGS) techniques has helped identify somatic gene mutations in 75–80% of MDS, that cluster mainly in four functional groups, i.e. cytokine signaling (RAS genes), DNA methylation, (TET2, IDH1/2, DNMT3a genes) histone modifications (ASXL1 and EZH2 genes), and spliceosome (SF3B1 and SRSF2 genes) along with mutations of RUNX1 and TP 53 genes. Most of those mutations, except SF3B1 and TET2 mutations, are associated with an overall poorer prognosis, while some gene mutations (mainly TET2 mutation), may be associated to better response to hypomethylating agents. The frequent mutations of epigenetic modulators in MDS appear to largely contribute to the importance of epigenetic deregulation (in particular gene hypermethylation and histone deacetylation) in MDS progression, and may account at least partially for the efficacy of hypomethylating agents in the treatment of MDS.
Summary
The diagnosis of Waldenström Macroglobulinaemia (WM)/lymphoplasmacytic lymphoma (LPL) remains one of exclusion because other B‐cell lymphoproliferative disorders (B‐LPD), such as marginal ...zone lymphoma (MZL), can fulfil similar criteria, including MYD88 L265P mutation. It has been suggested that expression of the myeloid marker CD13 (also termed ANPEP) is more frequent in LPL than in other B‐LPD and has also been described on normal and malignant plasma cells. Here, CD13 expression was tested in a cohort of 1037 B‐LPD patients from 3 centres by flow cytometry. The percentage of CD13‐expressing cells was found to be variable among B‐LPD but significantly higher in WM/LPL (median 31% vs. 0% in non‐WM/LPL, P < 0·001). In multivariate linear regression, CD13 expression remained significantly associated with a diagnosis of WM/LPL (P < 0·001). A cut‐off value of 2% of CD19+ cells co‐expressing CD13 yielded the best diagnostic performance for WM/LPL assertion. This was further improved by association with the presence or absence of IgM paraprotein. Finally, given that previously published transcriptomic data revealed no difference in CD13 (also termed ANPEP) mRNA between normal and pathological B‐cells, the hypothesis of some post‐transcriptional regulation must be favoured. These results suggest that testing for CD13 expression in routine flow cytometry panels could help to discriminate WM/LPL from other B‐LPD.
Background
Systemic inflammatory and autoimmune diseases (SIADs) occur in 10–20% of patients with myelodysplastic syndrome (MDS). Recently identified VEXAS (Vacuoles, E1 enzyme, X-linked, ...Autoinflammatory, Somatic) syndrome, associated with somatic mutations in
UBA1
(Ubiquitin-like modifier-activating enzyme 1), encompasses a range of severe inflammatory conditions along with hematological abnormalities, including MDS. The pathophysiological mechanisms underlying the association between MDS and SIADs remain largely unknown, especially the roles of different myeloid immune cell subsets. The aim of this study was to quantitatively evaluate peripheral blood myeloid immune cells (dendritic cells (DC) and monocytes) by flow cytometry in MDS patients with associated SIAD (
n
= 14, most often including relapsing polychondritis or neutrophilic dermatoses) and to compare their distribution in MDS patients without SIAD (
n
= 23) and healthy controls (
n
= 7). Most MDS and MDS/SIAD patients had low-risk MDS. Eight of 14 (57%) MDS/SIAD patients carried
UBA1
somatic mutations, defining VEXAS syndrome.Compared with MDS patients, most DC and monocyte subsets were significantly decreased in MDS/SIAD patients, especially in MDS patients with VEXAS syndrome. Our study provides the first overview of the peripheral blood immune myeloid cell distribution in MDS patients with associated SIADs and raises several hypotheses: possible redistribution to inflammation sites, increased apoptosis, or impaired development in the bone marrow.
Myelodysplastic syndromes (MDS) are heterogeneous hematopoietic stem cell malignancies that can phenotypically resemble other hematologic disorders. Thus, tools that may add to current diagnostic ...practices could aid in disease discrimination. Constitutive innate immune activation is a pathogenetic driver of ineffective hematopoiesis in MDS through Nod-like receptor protein 3 (NLRP3)–inflammasome-induced pyroptotic cell death. Oxidized mitochondrial DNA (ox-mtDNA) is released upon cytolysis, acts as a danger signal, and triggers inflammasome oligomerization via DNA sensors. By using immortalized bone marrow cells from murine models of common MDS somatic gene mutations and MDS primary samples, we demonstrate that ox-mtDNA is released upon pyroptosis. ox-mtDNA was significantly increased in MDS peripheral blood (PB) plasma compared with the plasma of healthy donors, and it was significantly higher in lower-risk MDS vs higher-risk MDS, consistent with the greater pyroptotic cell fraction in lower-risk patients. Furthermore, ox-mtDNA was significantly higher in MDS PB plasma compared with all other hematologic malignancies studied, with the exception of chronic lymphocytic leukemia (CLL). Receiver operating characteristic/area under the curve (ROC/AUC) analysis demonstrated that ox-mtDNA is a sensitive and specific biomarker for patients with MDS compared with healthy donors (AUC, 0.964), other hematologic malignancies excluding CLL (AUC, 0.893), and reactive conditions (AUC, 0.940). ox-mtDNA positively and significantly correlated with levels of known alarmins S100A9, S100A8, and apoptosis-associated speck-like protein containing caspase recruitment domain (CARD) specks, which provide an index of medullary pyroptosis. Collectively, these data indicate that quantifiable ox-mtDNA released into the extracellular space upon inflammasome activation serves as a biomarker for MDS and the magnitude of pyroptotic cell death.
•ox-mtDNA is released from cells after lytic, pyroptotic cell death and is readily quantifiable in cell supernatants and patient plasma.•PB plasma glucose–adjusted ox-mtDNA concentration is a sensitive and specific biomarker for MDS and medullary cell death.
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The stem cell factor receptor (SCF) c-Kit plays a pivotal role in regulating cell proliferation and survival in many cell types. In particular, c-Kit is required for early amplification of erythroid ...progenitors, while it must disappear from cell surface for the cell entering the final steps of maturation in an erythropoietin-dependent manner. We initially observed that imatinib (IM), an inhibitor targeting the tyrosine kinase activity of c-Kit concomitantly down-regulated the expression of c-Kit and accelerated the Epo-driven differentiation of erythroblasts in the absence of SCF. We investigated the mechanism by which IM or related masitinib (MA) induce c-Kit down-regulation in the human UT-7/Epo cell line. We found that the down-regulation of c-Kit in the presence of IM or MA was inhibited by a pre-incubation with methyl-β-cyclodextrin suggesting that c-Kit was internalized in the absence of ligand. By contrast to SCF, the internalization induced by TKI was independent of the E3 ubiquitin ligase c-Cbl. Furthermore, c-Kit was degraded through lysosomal, but not proteasomal pathway. In pulse-chase experiments, IM did not modulate c-Kit synthesis or maturation. Analysis of phosphotyrosine peptides in UT-7/Epo cells treated or not with IM show that IM did not modify overall tyrosine phosphorylation in these cells. Furthermore, we showed that a T670I mutation preventing the full access of IM to the ATP binding pocket, did not allow the internalization process in the presence of IM. Altogether these data show that TKI-induced internalization of c-Kit is linked to a modification of the integrity of ATP binding pocket.
Ten-eleven translocation 2 (TET2) mutations have been involved in myeloid malignancies. This retrospective study aims at evaluating the frequency and impact of TET2 mutations in 247 secondary acute ...myeloid leukemia cases referred to as myelodysplasia-related changes (n=201) or therapy-related (n=46) leukemias. Mutation of at least one copy of the TET2 gene was detected in 49 of 247 (19.8%) patients who presented with older age, higher hemoglobin level, higher neutrophil and monocyte counts, and lower platelet count. TET2 mutations were significantly less frequent in therapy-related (8.7%) than myelodysplasia-related changes (22.3%; P=0.035) leukemias and strongly associated with normal karyotype (P<0.001). TET2 mutations did not significantly associate with NPM1, FLT3-ITD or FLT3-D835, WT1, or N- or K-RAS mutations. Complete remission was achieved in 57% of evaluable patients who had received intensive chemotherapy. In this group, TET2 mutations did not influence the complete remission rate or overall survival.
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