Transcriptome analysis of bone marrow mesenchymal stromal cells from patients with primary myelofibrosis

International audiencePrimary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm whose severity and treatment complexity are attributed to the presence of bone marrow (BM) fibrosis and alterations of stroma impairing the production of normal blood cells. Despite the recently discovered mutations including the JAK2V617F mutation in about half of patients, the primitive event responsible for the clonal proliferation is still unknown. In the highly inflammatory context of PMF, the presence of fibrosis associated with a neoangiogenesis and an osteosclerosis concomitant to the myeloproliferation and to the increase number of circulating hematopoietic progenitors suggests that the crosstalk between hematopoietic and stromal cells is deregulated in the PMF BM microenvironmental niches. Within these niches, mesenchymal stromal cells (BM-MSC) play a hematopoietic supportive role in the production of growth factors and extracellular matrix which regulate the proliferation, differentiation, adhesion and migration of hematopoietic stem/progenitor cells. A transcriptome analysis of BM-MSC in PMF patients will help to characterize their molecular alterations and to understand their involvement in the hematopoietic stem/progenitor cell deregulation that features PMF

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PARIS7-Xavier Bichat (751182101) / SudocPARIS-Bib. Serv.Santé Armées (751055204) / SudocSudocFranceF

Hb Hope [β136Gly→Asp] and Hb Grady [α119_120insGluPheThr] compound heterozygosity in a Mauritanian patient

International audienc

Hepatitis E and Allogeneic Hematopoietic Stem Cell Transplantation: A French Nationwide SFGM-TC Retrospective Study

International audienceUsually self-limited, hepatitis E virus (HEV) infection may evolve to chronicity and cirrhosis in immunosuppressed patients. HEV infection has been described in solid-organ transplantation and hematology patients, but for allogeneic hematopoietic stem cell transplant (alloHSCT) recipients, only small cohorts are available. This retrospective nationwide multi-center series aimed to describe HEV diagnostic practices in alloHSCT French centers, and the course of infection in the context of alloHSCT. Twenty-nine out of 37 centers participated. HEV search in case of liver function tests (LFT) abnormalities was never performed in 24% of centers, occasionally in 55%, and systematically in 21%. Twenty-five cases of active HEV infection were diagnosed in seven centers, all because of LFT abnormalities, by blood nucleic acid testing. HEV infection was diagnosed in three patients before alloHSCT; HEV infection did not influence transplantation planning, and resolved spontaneously before or after alloHSCT. Twenty-two patients were diagnosed a median of 283 days after alloHSCT. Nine patients (41%) had spontaneous viral clearance, mostly after immunosuppressive treatment decrease. Thirteen patients (59%) received ribavirin, with sustained viral clearance in 11/12 evaluable patients. We observed three HEV recurrences but no HEV-related death or liver failure, nor evolution to cirrhosis

Hematopoietic Recovery using Multi-Cytokine Therapy in 8 Patients Presenting Radiation-Induced Myelosuppression after Radiological Accidents

International audienceTreatment of accidental radiation-induced myelosuppressionis primarily based on supportive care and requiresspecific treatment based on hematopoietic growth factorsinjection or hematopoietic cell transplantation for the mostsevere cases. The cytokines used consisted of pegylatederythropoietin (darbepoetin alfa) 500 IU once per week,pegylated G-CSF (pegfilgrastim) 6 mg 3 2 once, stem cellfactor 20 lg.kg–1 for five days, and romiplostim (TPO analog)10 lg.kg1 once per week, with different combinationsdepending on the accidents. As the stem cell factor did nothave regulatory approval for clinical use in France, theFrench regulatory authorities (ANSM, formerly, AFSSAPS)approved their compassionate use as an investigational drug‘‘on a case-by-case basis’’. According to the evolution andclinical characteristics, each patient’s treatment was adoptedon an individual basis. Daily blood count allows initiating GCSFand SCF delivery when granulocyte ,1,000/mm3, TPOdelivery when platelets ,50,000/mm3, and EPO when Hb,80g/L. The length of each treatment was based on blood cellrecovery criteria. The concept of ‘‘stimulation strategy’’ islinked to each patient’s residual hematopoiesis, which variesamong them, depending on the radiation exposure’s characteristicsand heterogeneity. This paper reports the medicalmanagement of 8 overexposed patients to ionizing radiation.The recovery of bone marrow function after myelosuppressionwas accelerated using growth factors, optimized bymultiple-line combinations. Particularly in the event ofprolonged exposure to ionizing radiation in dose ranges inducing severe myelosuppression (in the order of 5 to 8 Gy),with no indication of hematopoietic stem cell transplantation

Osteogenic Potential of Mesenchymal Stromal Cells Contributes to Primary Myelofibrosis.

International audiencePrimary myelofibrosis is a myeloproliferative neoplasm that is a precursor to myeloid leukemia. Dysmegakaryopoiesis and extramedullary hematopoiesis characterize primary myelofibrosis, which is also associated with bone marrow stromal alterations marked by fibrosis, neoangiogenesis, and osteomyelosclerosis. In particular, contributions to primary myelofibrosis from mesenchymal stromal cells (MSC) have been suggested by mouse studies, but evidence in humans remains lacking. In this study, we show that bone marrow MSCs from primary myelofibrosis patients exhibit unique molecular and functional abnormalities distinct from other myeloproliferative neoplasms and these abnormalities are maintained stably ex vivo in the absence of leukemic cells. Primary myelofibrosis-MSC overexpressed heparin-binding cytokines, including proinflammatory TGFβ1 and osteogenic BMP-2, as well as glycosaminoglycans such as heparan sulfate and chondroitin sulfate. Transcriptome and functional analyses revealed alterations in MSC differentiation characterized by an increased osteogenic potential and a TGFβ1 signaling signature. Accordingly, phospho-Smad2 levels were intrinsically increased in primary myelofibrosis-MSC along with enhanced expression of the master bone regulator RUNX2, while inhibition of the endogenous TGFβ1 receptor TGFβR1 impaired osteogenic differentiation in these MSCs. Taken together, our results define the source of a critical osteogenic function in primary myelofibrosis that supports its pathophysiology, suggesting that combined targeting of both the hematopoietic and stromal cell compartments in primary myelofibrosis patients may heighten therapeutic efficacy. Cancer Res; 75(22); 4753-65. ©2015 AACR