Explore the vast range of titles available.

Myelodysplastic syndromes are clonal marrow stem-cell disorders, characterised by ineffective haemopoiesis leading to blood cytopenias, and by progression to acute myeloid leukaemia in a third of patients. 15% of cases occur after chemotherapy or radiotherapy for a previous cancer; the syndromes are most common in elderly people. The pathophysiology involves cytogenetic changes with or without gene mutations and widespread gene hypermethylation at advanced stages. Clinical manifestations result from cytopenias (anaemia, infection, and bleeding). Diagnosis is based on examination of blood and bone marrow showing blood cytopenias and hypercellular marrow with dysplasia, with or without excess of blasts. Prognosis depends largely on the marrow blast percentage, number and extent of cytopenias, and cytogenetic abnormalities. Treatment of patients with lower-risk myelodysplastic syndromes, especially for anaemia, includes growth factors, lenalidomide, and transfusions. Treatment of higher-risk patients is with hypomethylating agents and, whenever possible, allogeneic stem-cell transplantation.

Hyperleukocytosis in acute myeloid leukemia (AML) is associated with inferior outcomes. There is limited high quality evidence to support the benefits of leukapheresis. We retrospectively collected data from patients with newly-diagnosed AML who presented with a white cell count (WBC) >50 × 109/L to 12 centers in the United States and Europe from 2006 to 2017 and received intensive chemotherapy. Logistic regression models estimated odds ratios for 30-day mortality and achievement of composite complete remission (CRc). Cox proportional hazard models estimated hazard ratios for overall survival (OS). Among 779 patients, clinical leukostasis was reported in 27%, and leukapheresis was used in 113 patients (15%). Thirty-day mortality was 16.7% (95% CI: 13.9–19.3%). Median OS was 12.6 months (95% CI: 11.5–14.9) among all patients, and 4.5 months (95% CI: 2.7–7.1) among those ≥65 years. Use of leukapheresis did not significantly impact 30-day mortality, achievement of CRc, or OS in multivariate analysis based on available data or in analysis based on multiple imputation. Among patients with investigator-adjudicated clinical leukostasis, there were statistically significant improvements in 30-day mortality and OS with leukapheresis in unadjusted analysis, but not in multivariate analysis. Given the significant resource use, cost, and potential complications of leukapheresis, randomized studies are needed to evaluate its value.

Islands of CD123 high cells have been commonly described in the bone marrow of patients with chronic myelomonocytic leukemia (CMML). Using a multiparameter flow cytometry assay, we detected an excess of CD123 + mononucleated cells that are lineage-negative, CD45 + , CD11c − , CD33 − , HLA-DR + , BDCA-2 + , BDCA-4 + in the bone marrow of 32/159 (20%) patients. Conventional and electron microscopy, flow cytometry detection of cell surface markers, gene expression analyses, and the ability to synthesize interferon alpha in response to Toll-like receptor agonists identified these cells as bona fide plasmacytoid dendritic cells (pDCs). Whole-exome sequencing of sorted monocytes and pDCs identified somatic mutations in genes of the oncogenic RAS pathway in the two cell types of every patient. CD34 + cells could generate high amount of pDCs in the absence of FMS-like tyrosine kinase 3-ligand (FLT3L). Finally, an excess of pDCs correlates with regulatory T cell accumulation and an increased risk of acute leukemia transformation. These results demonstrate the FLT3L-independent accumulation of clonal pDCs in the bone marrow of CMML patients with mutations affecting the RAS pathway, which is associated with a higher risk of disease progression.

Calcium is a ubiquitous messenger that regulates a wide range of cellular functions, but its involvement in the pathophysiology of acute myeloid leukemia (AML) is not widely investigated. Here, we identified, from an analysis of The Cancer Genome Atlas and genotype‐tissue expression databases, stromal interaction molecule 2 (STIM2) as being highly expressed in AML with monocytic differentiation and negatively correlated with overall survival. This was confirmed on a validation cohort of 407 AML patients. We then investigated the role of STIM2 in cell proliferation, differentiation, and survival in two leukemic cell lines with monocytic potential and in normal hematopoietic stem cells. STIM2 expression increased at the RNA and protein levels upon monocyte differentiation. Phenotypically, STIM2 knockdown drastically inhibited cell proliferation and induced genomic stress with DNA double‐strand breaks, as shown by increased levels of phosphorylate histone H2AXγ (p‐H2AXγ), followed by activation of the cellular tumor antigen p53 pathway, decreased expression of cell cycle regulators such as cyclin‐dependent kinase 1 (CDK1)–cyclin B1 and M‐phase inducer phosphatase 3 (CDC25c), and a decreased apoptosis threshold with a low antiapoptotic/proapoptotic protein ratio. Our study reports STIM2 as a new actor regulating genomic stability and p53 response in terms of cell cycle and apoptosis of human normal and malignant monocytic cells. This research uncovers an important role of STIM2 in the proliferation and survival of normal and malignant monocytic cells. STIM2 knockdown in both cell type leads to decreased cell proliferation and survival through induction of genotoxic stress and induction of p53, leading to cell cycle block and apoptosis in both cell types. STIM2 may be a potential target in AML treatment.

We retrospectively reviewed all medical charts from patients admitted to Saint-Louis Hospital between January, 1.sup.st 1997 and December, 31st 2018 with newly diagnosed AML and white blood cell (WBC) count above 50x10.sup.9 /L. Outcome measures were cumulative incidence of relapse (CIR), treatment-related mortality (TRM) defined as relapse-free death, and overall survival. Univariate and multivariate analyses were performed using Cox proportional hazards models. A total of 184 patients with HL AML in complete remission (CR) were included in this study. At 2 years after CR. 62.5% of patients were alive, at 5 years, cumulated incidence of relapse was 55.8%. We found that every therapeutic measure, including life-sustaining therapies carried out in the initial phase of the disease, did not increase the relapse risk. The use of hydroxyurea for more than 4 days was associated with a higher risk of relapse. At the end of the study, 94 patients (51.1%) were still alive including 23 patients out of 44 aged less than 60 yo that were able to return to work. We show that the use of emergency measures including life sustaining therapies does not come at the expense of a higher risk of relapse or mortality, except in the case of prolonged use of hydroxyurea. Patients with HL AML should be able to benefit from all available techniques, regardless of their initial severity.

Chronic myelomonocytic leukemia (CMML) is a severe myeloid malignancy with limited therapeutic options. Single-cell analysis of clonal architecture demonstrates early clonal dominance with few residual WT hematopoietic stem cells. Circulating myeloid cells of the leukemic clone and the cytokines they produce generate a deleterious inflammatory climate. Our hypothesis is that therapeutic control of the inflammatory component in CMML could contribute to stepping down disease progression. The present study explored the contribution of immature granulocytes (iGRANs) to CMML progression. iGRANs were detected and quantified in the peripheral blood of patients by spectral and conventional flow cytometry. Their accumulation was a potent and independent poor prognostic factor. These cells belong to the leukemic clone and behaved as myeloid-derived suppressor cells. Bulk and single-cell RNA-Seq revealed a proinflammatory status of iGRAN that secreted multiple cytokines of which CXCL8 was at the highest level. This cytokine inhibited the proliferation of WT but not CMML hematopoietic stem and progenitor cells (HSPCs) in which CXCL8 receptors were downregulated. CXCL8 receptor inhibitors and CXCL8 blockade restored WT HSPC proliferation, suggesting that relieving CXCL8 selective pressure on WT HSPCs is a potential strategy to slow CMML progression and restore some healthy hematopoiesis.

Chronic myelomonocytic leukemia (CMML) was named 50 years ago to describe a myeloid malignancy whose onset is typically insidious. This disease is now classified by the World Health Organisation as a myelodysplastic syndrome (MDS)-myeloproliferative neoplasm (MPN) overlap disease. Observed mostly in ageing people, CMML is characterized by the expansion of monocytes and, in many cases, granulocytes. Abnormal repartition of circulating monocyte subsets, as identified by flow cytometry, facilitates disease recognition. CMML is driven by the accumulation, in the stem cell compartment, of somatic variants in epigenetic, splicing and signaling genes, leading to epigenetic reprogramming. Mature cells of the leukemic clone contribute to creating an inflammatory climate through the release of cytokines and chemokines. The suspected role of the bone marrow niche in driving CMML emergence and progression remains to be deciphered. The clinical expression of the disease is highly diverse. Time-dependent accumulation of symptoms eventually leads to patient death as a consequence of physical exhaustion, multiple cytopenias and acute leukemia transformation. Fifty years after its identification, CMML remains one of the most severe chronic myeloid malignancies, without disease-modifying therapy. The proliferative component of the disease that distinguishes CMML from severe MDS has been mostly neglected. This review summarizes the progresses made in disease understanding since its recognition and argues for more CMML-dedicated clinical trials.

Non-classical monocyte subsets may derive from classical monocyte differentiation and the proportion of each subset is tightly controlled. Deregulation of this repartition is observed in diverse human diseases, including chronic myelomonocytic leukemia (CMML) in which non-classical monocyte numbers are significantly decreased relative to healthy controls. Here, we identify a down-regulation of hsa-miR-150 through methylation of a lineage-specific promoter in CMML monocytes. Mir150 knock-out mice demonstrate a cell-autonomous defect in non-classical monocytes. Our pulldown experiments point to Ten-Eleven-Translocation-3 (TET3) mRNA as a hsa-miR-150 target in classical human monocytes. We show that Tet3 knockout mice generate an increased number of non-classical monocytes. Our results identify the miR-150/TET3 axis as being involved in the generation of non-classical monocytes. A decrease in the fraction of non-classical monocytes is a hallmark of chronic myelomonocytic leukaemia. Taking advantage of this abnormal situation, the authors identify a mechanistic link between miR-150 and TET3 as being involved in monocyte subset generation.