Major T Cell Progenitor Activity in Bone Marrow–derived Spleen Colonies

Common lymphoid progenitors (CLP) are generated in adult bone marrow (BM), but the intermediate steps leading to T cell commitment are unknown, and so is the site at which this commitment occurs. Here, we show that colonies arising in the spleen 12 days after BM injection harbor T cell precursors that are undetectable in BM. These precursors did not generate myeloid cells in vivo but repopulated the thymus and the peripheral T cell compartment much faster than did CLP. Two lineage negative (Lin−) subpopulations were distinguished, namely CD44+ Thy1− cells still capable of natural killer generation and transient low-level B cell generation, and T cell–restricted CD44− Thy1+ cells. At a molecular level, frequency of CD3ɛ and preTα mRNA was very different in each subset. Furthermore, only the CD44− Thy1+ subset have initiated rearrangements in the T cell receptor β locus. Thus, this study identifies extramedullary T cell progenitors and will allow easy approach to T cell commitment studies

Ptk7-Deficient Mice Have Decreased Hematopoietic Stem Cell Pools as a Result of Deregulated Proliferation and Migration

International audienceHematopoietic stem cells (HSCs) located in adult bone marrow or fetal liver in mammals produce all cells from the blood system. Atthe top of the hierarchy are long-term HSCs endowed with lifelong self-renewal and differentiation properties. These features arecontrolled through key microenvironmental cues and regulatory pathways, such as Wnt signaling.We showed previously that PTK7,a tyrosine kinase receptor involved in planar cell polarity, plays a role in epithelial Wnt signaling; however, its function in hematopoiesishas remained unexplored. In this article, we show that PTK7 is expressed by hematopoietic stem and progenitor cells, withthe highest level of protein expression found on HSCs. Taking advantage of a Ptk7-deficient mouse strain, we demonstrate that loss ofPtk7 leads to a diminished pool of HSCs but does not affect in vitro or in vivo hematopoietic cell differentiation. This is correlatedwith increased quiescence and reduced homing abilities of Ptk7-deficient hematopoietic stem and progenitor cells, unraveling noveland unexpected functions for planar cell polarity pathways in HSC fate

Ontogenic Changes in Hematopoietic Hierarchy Determine Pediatric Specificity and Disease Phenotype in Fusion Oncogene-Driven Myeloid Leukemia.

Fusion oncogenes are prevalent in several pediatric cancers, yet little is known about the specific associations between age and phenotype. We observed that fusion oncogenes, such as ETO2-GLIS2, are associated with acute megakaryoblastic or other myeloid leukemia subtypes in an age-dependent manner. Analysis of a novel inducible transgenic mouse model showed that ETO2-GLIS2 expression in fetal hematopoietic stem cells induced rapid megakaryoblastic leukemia whereas expression in adult bone marrow hematopoietic stem cells resulted in a shift toward myeloid transformation with a strikingly delayed in vivo leukemogenic potential. Chromatin accessibility and single-cell transcriptome analyses indicate ontogeny-dependent intrinsic and ETO2-GLIS2-induced differences in the activities of key transcription factors, including ERG, SPI1, GATA1, and CEBPA. Importantly, switching off the fusion oncogene restored terminal differentiation of the leukemic blasts. Together, these data show that aggressiveness and phenotypes in pediatric acute myeloid leukemia result from an ontogeny-related differential susceptibility to transformation by fusion oncogenes. SIGNIFICANCE: This work demonstrates that the clinical phenotype of pediatric acute myeloid leukemia is determined by ontogeny-dependent susceptibility for transformation by oncogenic fusion genes. The phenotype is maintained by potentially reversible alteration of key transcription factors, indicating that targeting of the fusions may overcome the differentiation blockage and revert the leukemic state.See related commentary by Cruz Hernandez and Vyas, p. 1653.This article is highlighted in the In This Issue feature, p. 1631

Analyse d'une voie de différenciation T identifiée dans les colonies spléniques

Les lymphocytes T sont générés dans le thymus, à partir de progéniteurs originaires de la moelle osseuse : les cellules souches hématopoïétiques. Au cours de leur maturation , les CHS vont être capables de générer toutes les cellules du système sanguin . Dans le cas de la lignée T, les progéniteurs hématopoïétiques doivent d'abord coloniser le thymus pour se différencier en lymphocytes T. Une des grandes questions est quel progéniteur de la moelle osseuse migre dans le thymus et est à l'origine des progéniteurs intrathymiques. L'identification dans la moelle osseuse d'une population de progéniteurs capable de géne rer toutes les cellules de la lignée lymphoïde a laissé penser que ces cellules, les CLP, étaient à l'origine des progéniteurs intrathymiques. Toutefois, le fait que cette population ne puisse migrer dans le sang rend cette hypothèse difficile. Ainsi, les progéniteurs de la moelle à l'origine des progéniteurs intrathymiques fait sans doute parti de la population Lin Sca-1+c-kit hi (LSK). Une autre question importante concerne les sites et les mécanismes de restriction à la lignée TPARIS5-BU-Necker : Fermée (751152101) / SudocSudocFranceF

Molecular dynamics of myeloid progenitor transformation

International audienceAcute myeloid leukaemia (AML) is the most common acute leukaemia in adults. AML results from the accumulation of abnormal immature myeloid progenitors, also called blasts, that are blocked in their differentiation. AML is a very heterogeneous disease with more than a dozen of genetically distinct entities (See new AML classification from [1]). Each genetically distinct AML subgroup is generally defined by gene mutations and/or alterations related to its aggressiveness, and is associated to [...

The thymus exports long-lived fully committed T cell precursors that can colonize primary lymphoid organs

International audienceThymic export of cells is believed to be restricted to mature T cells. Here we show that the thymus also exports fully committed T cell precursors that colonize primary lymphoid organs. These precursor cells exited the thymus before T cell receptor rearrangements and colonized lymphoid organs such as the thymus and the gut. Migration of the thymic T cell–committed precursors led to permanent colonization of the gut precursor compartment, improved the capacity of gut precursors to further differentiate into T cells and was sufficient for the generation of 'euthymic like' CD8αα+ intraepithelial lymphocytes. These data demonstrate a new function for the thymus in peripheral seeding with T cell precursors that become long lived after thymus export

Dok1 and Dok2 proteins regulate cell cycle in hematopoietic stem and progenitor cells : Dok1 and Dok2 regulate HSPC cell cycle

International audienceDok1 and Dok2 proteins play a crucial role in myeloid cell proliferation as demonstrated by Dok1 and Dok2 gene inactivation, which induces a myeloproliferative disease in aging mice. In this study, we show that Dok1/Dok2-deficiency affects myeloproliferation even at a young age. An increase in the cellularity of multipotent progenitors (MPP) is observed in young Dok1/Dok2-deficient mice. This is associated with an increase in the cells undergoing cell cycle, which is restricted to myeloid committed progenitors. Furthermore, cellular stress triggered by 5-Fluoro Uracil (5-FU) treatment, potentiates the effects of the loss of Dok proteins on MPP cell cycle. In addition, Dok1/Dok2 deficiency induces resistance to 5-FU induced hematopoietic stem cell (HSC) exhaustion. Taken together, these results demonstrate that Dok1 and Dok2 proteins are involved in the control of HSC cell cycle regulation