Oxidative Phosphorylation Fueled by Fatty Acid Oxidation Sensitizes Leukemic Stem Cells to Cold

Dependency on mitochondrial oxidative phosphorylation (OxPhos) is a potential weakness for leukemic stem cells (LSC) that can be exploited for therapeutic purposes. Fatty acid oxidation (FAO) is a crucial OxPhos-fueling catabolic pathway for some acute myeloid leukemia (AML) cells, particularly chemotherapy-resistant AML cells. Here, we identified cold sensitivity at 4◦C (cold killing challenge; CKC4), commonly used for sample storage, as a novel vulnerability that selectively kills AML LSCs with active FAO-supported OxPhos while sparing normal hematopoietic stem cells. Cell death of OxPhos-positive leukemic cells was induced by membrane permeabilization at 4◦C; by sharp contrast, leukemic cells relying on glycolysis were resistant. Forcing glycolytic cells to activate OxPhos metabolism sensitized them to CKC4. Lipidomic and proteomic analyses showed that OxPhos shapes the composition of the plasma membrane and introduces variation of 22 lipid subfamilies between cold-sensitive and cold-resistant cells. Together, these findings indicate that steady-state energy metabolism at body temperature predetermines the sensitivity of AML LSCs to cold temperature, suggesting that cold sensitivity could be a potential OxPhos biomarker. These results could have important implications for designing experiments for AML research to avoid cell storage at 4◦C.</p

Myeloid cell differentiation arrest by miR-125b-1 in myelodysplasic syndrome and acute myeloid leukemia with the t(2;11)(p21;q23) translocation

Most chromosomal translocations in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) involve oncogenes that are either up-regulated or form part of new chimeric genes. The t(2;11)(p21;q23) translocation has been cloned in 19 cases of MDS and AML. In addition to this, we have shown that this translocation is associated with a strong up-regulation of miR-125b (from 6- to 90-fold). In vitro experiments revealed that miR-125b was able to interfere with primary human CD34+ cell differentiation, and also inhibited terminal (monocytic and granulocytic) differentiation in HL60 and NB4 leukemic cell lines. Therefore, miR-125b up-regulation may represent a new mechanism of myeloid cell transformation, and myeloid neoplasms carrying the t(2;11) translocation define a new clinicopathological entity

The CADM1 tumor suppressor gene is a major candidate gene in MDS with deletion of the long arm of chromosome 11.

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis leading to peripheral cytopenias and in a substantial proportion of cases to acute myeloid leukemia. The deletion of the long arm of chromosome 11, del(11q), is a rare but recurrent clonal event in MDS. Here, we detail the largest series of 113 cases of MDS and myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) harboring a del(11q) analyzed at clinical, cytological, cytogenetic, and molecular levels. Female predominance, a survival prognosis similar to other MDS, a low monocyte count, and dysmegakaryopoiesis were the specific clinical and cytological features of del(11q) MDS. In most cases, del(11q) was isolated, primary and interstitial encompassing the 11q22-23 region containing ATM, KMT2A, and CBL genes. The common deleted region at 11q23.2 is centered on an intergenic region between CADM1 (also known as Tumor Suppressor in Lung Cancer 1) and NXPE2. CADM1 was expressed in all myeloid cells analyzed in contrast to NXPE2. At the functional level, the deletion of Cadm1 in murine Lineage-Sca1+Kit+ cells modifies the lymphoid-to-myeloid ratio in bone marrow, although not altering their multilineage hematopoietic reconstitution potential after syngenic transplantation. Together with the frequent simultaneous deletions of KMT2A, ATM, and CBL and mutations of ASXL1, SF3B1, and CBL, we show that CADM1 may be important in the physiopathology of the del(11q) MDS, extending its role as tumor-suppressor gene from solid tumors to hematopoietic malignancies

Between but not within species variation in the distribution of fitness effects

New mutations provide the raw material for evolution and adaptation. The distribution of fitness effects (DFE) describes the spectrum of effects of new mutations that can occur along a genome, and is therefore of vital interest in evolutionary biology. Recent work has uncovered striking similarities in the DFE between closely related species, prompting us to ask whether there is variation in the DFE among populations of the same species, or among species with different degrees of divergence, i.e., whether there is variation in the DFE at different levels of evolution. Using exome capture data from six tree species sampled across Europe we characterised the DFE for multiple species, and for each species, multiple populations, and investigated the factors potentially influencing the DFE, such as demography, population divergence and genetic background. We find statistical support for there being variation in the DFE at the species level, even among relatively closely related species. However, we find very little difference at the population level, suggesting that differences in the DFE are primarily driven by deep features of species biology, and that evolutionarily recent events, such as demographic changes and local adaptation, have little impact

Etude du récepteur soluble de la transferrine et de la dysérythropoïèse chez 60 patients atteints de syndrome myélodysplasique

Les syndromes myélodysplasiques (SMD) sont des affections hématologiques du sujet, caractérisées particulièrement par une érythropoïèse inefficace ou dysérythropoïèse ayant pour conséquence l'existence d'une anémie chez 80% de ces malades. Le récepteur soluble de la transferrine (RSTf) est initialement un marqueur du statut martial, mais il été montré que ce récepteur est également corrélé à l'activité érythropoïétique de la moelle osseuse, notamment chez les patients ayant un SMD. Cette étude a pour objectif de rechercher si une corrélation existe entre le taux de RSTf et la dysérythropoïèse (évaluée par plusieurs critères) chez les patients atteint de SMD, et de comparer le taux de RSTf et la dysérythropoïèse entre les SMD de bas risque et les SMD de haut risque. Pour cela, nous avons étudié une cohorte de 60 patients atteints de SMD, et nous les avons comparés entre eux et également à un groupe témoin, pour le RSTf et pour la dysérythropoïèse. Nos résultats montrent que la valeur du RSTf reflète l'intensité de la dysréythropoïèse ; elle est significativement plus élevée chez les patients ayant un SMD avec une dysérythropoïèse importante. Nous avons également montré qu'il existait une corrélation entre la valeur du RSTf et l'intensité de la dysérythropoïèse, mais seulement dans les SMD de faible risque.En conclusion, notre travail suggère que le RSTf peut être un marqueur de dysérythropoïèse dans les SMD de bas risque. Ces résultats doivent être confirmés par des études complémentaires portant sur des cohortes plus conséquentes.TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF

Régulation de la télomérase dans les cellules hématopoïétiques normales et leucémiques

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

Régulation de la télomérase par le TNFa dans les cellules hématopoïétiques et leucémiques

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF