Progressive chromatin rewiring by ETO2::GLIS2 revealed in a human iPSC model of pediatric leukemia initiation.

Pediatric acute myeloid leukemia frequently harbor fusion oncogenes associated with poor prognosis, including KMT2A, NUP98 and GLIS2 rearrangements. While murine models have demonstrated their leukemogenic activities, the steps from a normal human cell to leukemic blasts remain unclear. Here, we precisely reproduced the inversion of chromosome 16 resulting in ETO2::GLIS2 fusion in human induced pluripotent stem cells (iPSC).

SRSF2-P95H decreases JAK/STAT signaling in hematopoietic cells and delays myelofibrosis development in mice.

Heterozygous mutation targeting proline 95 in Serine/Arginine-rich Splicing Factor 2 (SRSF2) is associated with V617F mutation in Janus Activated Kinase 2 (JAK2) in some myeloproliferative neoplasms (MPNs), most commonly primary myelofibrosis. To explore the interaction of Srsf2 with Jak2, we generated Cre-inducible knock-in mice expressing these mutants under control of the stem cell leukemia (Scl) gene promoter. In transplantation experiments, Srsf2 unexpectedly delayed myelofibrosis induced by Jak2 and decreased TGFβ1 serum level.

Stepwise GATA1 and SMC3 mutations alter megakaryocyte differentiation in a Down syndrome leukemia model.

Acute megakaryoblastic leukemia of Down syndrome (DS-AMKL) is a model of clonal evolution from a preleukemic transient myeloproliferative disorder requiring both a trisomy 21 (T21) and a GATA1s mutation to a leukemia driven by additional driver mutations. We modeled the megakaryocyte differentiation defect through stepwise gene editing of GATA1s, SMC3+/-, and MPLW515K, providing 20 different T21 or disomy 21 (D21) induced pluripotent stem cell (iPSC) clones. GATA1s profoundly reshaped iPSC-derived hematopoietic architecture with gradual myeloid-to-megakaryocyte shift and megakaryocyte differentiation alteration upon addition of SMC3 and MPL mutations.

Aldehyde dehydrogenases contribute to skeletal muscle homeostasis in healthy, aging, and Duchenne muscular dystrophy patients.

Background: Aldehyde dehydrogenases (ALDHs) are key players in cell survival, protection, and differentiation via the metabolism and detoxification of aldehydes. ALDH activity is also a marker of stem cells. The skeletal muscle contains populations of ALDH-positive cells amenable to use in cell therapy, whose distribution, persistence in aging, and modifications in myopathic context have not been investigated yet.

Routine clinical use of circulating tumor cells for diagnosis of mutations and chromosomal rearrangements in non-small cell lung cancer-ready for prime-time?

In non-small cell lung cancer (NSCLC), diagnosis of predictive biomarkers for targeted therapies is currently done in small tumor biopsies. However, tumor biopsies can be invasive, in some cases associated with risk, and tissue adequacy, both in terms of quantity and quality is often insufficient. The development of efficient and non-invasive methods to identify genetic alterations is a key challenge which circulating tumor cells (CTCs) have the potential to be exploited for.

Detection of Gene Rearrangements in Circulating Tumor Cells: Examples of ALK-, ROS1-, RET-Rearrangements in Non-Small-Cell Lung Cancer and ERG-Rearrangements in Prostate Cancer.

Circulating tumor cells (CTCs) hold promise as biomarkers to aid in patient treatment stratification and disease monitoring. Because the number of cells is a critical parameter for exploiting CTCs for predictive biomarker's detection, we developed a FISH (fluorescent in situ hybridization) method for CTCs enriched on filters (filter-adapted FISH [FA-FISH]) that was optimized for high cell recovery. To increase the feasibility and reliability of the analyses, we combined fluorescent staining and FA-FISH and developed a semi-automated microscopy method for optimal FISH signal identification in filtration-enriched CTCs .

The Notch Delta-4 ligand helps to maintain the quiescence and the short-term reconstitutive potential of haematopoietic progenitor cells through activation of a key gene network.

Understanding the role of Notch and its ligands within the different bone marrow niches could shed light on the mechanisms regulating haematopoietic progenitor cells (HPCs) maintenance and self-renewal. Here, we report that murine bone marrow HPCs activation by the vascular Notch Delta-4 ligand maintains a significant proportion of cells specifically in the G0 state. Furthermore, Delta-4/Notch pathway limits significantly the loss of the in vivo short-term reconstitutive potential upon transplantation of Delta-4 activated HPCs into lethally irradiated recipient mice.

Myoblasts and embryonic stem cells differentially engraft in a mouse model of genetic dilated cardiomyopathy.

The functional and architectural benefits of embryonic stem cells (ESC) and myoblasts (Mb) transplantations into infarcted myocardium have been investigated extensively. Whereas ESC repopulated fibrotic areas and contributed to myocardial regeneration, Mb exerted their effects through paracrine secretions and scar remodeling. This therapeutic perspective, however, has been less explored in the setting of nonischemic dilated cardiomyopathies (DCMs).

Cell therapy for muscular dystrophies: advances and challenges.

Purpose Of Review: Cell therapy is considered a potential therapeutic avenue for the treatment of skeletal muscle diseases. Heterologous and autologous approaches have been attempted in the context, respectively, of generalized degenerative disease and of localized repairs. Cell transplantation trials, however, have been hampered by poor survival and limited migratory ability of the cells.

Notch/Delta4 signaling inhibits human megakaryocytic terminal differentiation.

The effects of Notch signaling on human megakaryocytic and erythroid differentiation were investigated by exposing human CD34(+) progenitor cells to an immobilized chimeric form of the Notch ligand, Delta-like4 (Dll4Fc). Exposure of human cord blood CD34(+) cells to Dll4Fc induced a modest enhancement of erythroid cell production. Conversely, under megakaryocytic culture conditions, Dll4Fc strongly impaired platelet production by reducing the generation of mature CD41a(+)CD42b(+) megakaryocytes (MKs) and platelet-forming cells.

Aldehyde dehydrogenase activity identifies a population of human skeletal muscle cells with high myogenic capacities.

Aldehyde dehydrogenase 1A1 (ALDH) activity is one hallmark of human bone marrow (BM), umbilical cord blood (UCB), and peripheral blood (PB) primitive progenitors presenting high reconstitution capacities in vivo. In this study, we have identified ALDH(+) cells within human skeletal muscles, and have analyzed their phenotypical and functional characteristics. Immunohistofluorescence analysis of human muscle tissue sections revealed rare endomysial cells.

Distinct effects of the soluble versus membrane-bound forms of the notch ligand delta-4 on human CD34+CD38low cell expansion and differentiation.

Although Notch ligands are considered to activate signaling through direct cell-cell contact, the existence of soluble forms has been demonstrated. However, their roles remain controversial: soluble forms have been reported to mimic the biological activity of membrane-bound form, whereas other studies rather suggested an antagonistic activity toward their full-length counterparts. We previously observed that membrane-bound Delta4-expressing S17 stroma (mbD4/S17) reduced human CD34+CD38(low) cell proliferation and favored self-renewal.

Notch/Delta4 interaction in human embryonic liver CD34+ CD38- cells: positive influence on BFU-E production and LTC-IC potential maintenance.

We investigated whether Notch signaling pathways have a role in human developmental hematopoiesis. In situ histochemistry analysis revealed that Notch1, 2, and 4 and Notch ligand (Delta1-4, and Jagged1) proteins were not expressed in the yolk sac blood islands, the para-aortic splanchnopleure, the hematopoietic aortic clusters, and at the early stages of embryonic liver hematopoiesis. Notch1-2, and Delta4 were eventually detected in the embryonic liver, from 34 until 38 days postconception.