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6. Megakaryocyte TGFβ1 partitions erythropoiesis into immature progenitor/stem cells and maturing precursors

Author

De Sepulveda, Paulo, Di Giandomenico, Silvana, Kermani, Pouneh, Mollé, Nicole, Yabut, Maria Mia, Abu-Zeinah, Ghaith, Stephens, Thomas, Messali, Nassima, Schreiner, Ryan, Brenet, Fabienne, Rafii, Shahin, Scandura, Joseph, Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Weill Medical College of Cornell University [New York], Aix Marseille Université (AMU)-Institut Paoli-Calmettes, and Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Hematopoiesis and Stem Cells, [SDV]Life Sciences [q-bio], Immunology, Apoptosis, Mice, Transgenic, Cell Count, Biology, Biochemistry, Immunophenotyping, Transforming Growth Factor beta1, 03 medical and health sciences, Gene Knockout Techniques, Mice, 0302 clinical medicine, Megakaryocyte, Bone Marrow, hemic and lymphatic diseases, medicine, Animals, Erythropoiesis, Progenitor cell, Erythropoietin, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Progenitor, Erythroid Precursor Cells, 0303 health sciences, Stem Cells, Cell Biology, Hematology, Hematopoietic Stem Cells, Recombinant Proteins, Cell biology, Mice, Inbred C57BL, Haematopoiesis, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Radiation Chimera, Stem cell, Megakaryocytes, Transforming growth factor, medicine.drug, Megakaryocyte-Erythroid Progenitor Cells
Abstract

Erythropoietin (EPO) provides the major survival signal to maturing erythroid precursors (EPs) and is essential for terminal erythropoiesis. Nonetheless, progenitor cells can irreversibly commit to an erythroid fate well before EPO acts, risking inefficiency if these progenitors are unneeded to maintain red blood cell (RBC) counts. We identified a new modular organization of erythropoiesis and, for the first time, demonstrate that the pre-EPO module is coupled to late EPO-dependent erythropoiesis by megakaryocyte (Mk) signals. Disrupting megakaryocytic transforming growth factor β1 (Tgfb1) disorganized hematopoiesis by expanding the pre-EPO pool of progenitor cells and consequently triggering significant apoptosis of EPO-dependent EPs. Similarly, pharmacologic blockade of TGFβ signaling in normal mice boosted the pre-EPO module, leading to apoptosis of EPO-sensitive EPs. Subsequent treatment with low-dose EPO triggered robust RBC production in both models. This work reveals modular regulation of erythropoiesis and offers a new strategy for overcoming chronic anemias.

Published
2020
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9. JAK2 V617FImpairs Lymphoid Differentiation in Myeloproliferative Neoplasms

Author

Choi, Daniel C, Abu-Zeinah, Ghaith, Kermani, Pouneh, Messali, Nassima, Yabut, Maria Mia, Erdos, Katie, and Scandura, Joseph M.

Abstract

Myeloproliferative neoplasms (MPNs) arise from the clonal acquisition of a driver mutation in a hematopoietic stem cell (HSC), often decades before the emergence of clinical disease. A defining characteristic of an HSC is its potential to give rise to both myeloid and lymphoid hematopoietic lineages. Yet the most common MPN driver mutation, JAK2 V617F, has only rarely been observed in lymphocytes. We conducted this study to determine why the JAK2 V617Fclone does not contribute to mature lymphocytes.

Published
2023
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