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Architectural and functional heterogeneity of hematopoietic stem/progenitor cells in non-del(5q) myelodysplastic syndromes

Virginie Chesnais, Marie-Laure Arcangeli, Caroline Delette, Alice Rousseau, Hélène Guermouche, Carine Lefevre, Sabrina Bondu, M’boyba Diop, Meyling Cheok, Nicolas Chapuis, Laurence Legros, Sophie Raynaud, Lise Willems, Didier Bouscary, Evelyne Lauret, Olivier A. Bernard, Olivier Kosmider, Françoise Pflumio and Michaela Fontenay

Key Points

  • Genetic heterogeneity in non-del(5q) MDS arises within the HSPC and in committed progenitors.

  • Clonal selection in lineage-committed progenitors may drive the transformation to acute myeloid leukemia.

Abstract

Myelodysplastic syndromes (MDSs) are hematopoietic stem cell disorders in which recurrent mutations define clonal hematopoiesis. The origin of the phenotypic diversity of non-del(5q) MDS remains unclear. Here, we investigated the clonal architecture of the CD34+CD38 hematopoietic stem/progenitor cell (HSPC) compartment and interrogated dominant clones for MDS-initiating cells. We found that clones mainly accumulate mutations in a linear succession with retention of a dominant subclone. The clone detected in the long-term culture-initiating cell compartment that reconstitutes short-term human hematopoiesis in xenotransplantation models is usually the dominant clone, which gives rise to the myeloid and to a lesser extent to the lymphoid lineage. The pattern of mutations may differ between common myeloid progenitors (CMPs), granulomonocytic progenitors (GMPs), and megakaryocytic-erythroid progenitors (MEPs). Rare STAG2 mutations can amplify at the level of GMPs, from which it may drive the transformation to acute myeloid leukemia. We report that major truncating BCOR gene mutation affecting HSPC and CMP was beneath the threshold of detection in GMP or MEP. Consistently, BCOR knock-down (KD) in normal CD34+ progenitors modifies their granulocytic and erythroid differentiation. Clonal architecture of the HSPC compartment and mutations selected during differentiation contribute to the phenotypic heterogeneity of MDS. Defining the hierarchy of driver mutations provides insights into the process of transformation and may guide the search for novel therapeutic strategies.

  • Submitted March 26, 2016.
  • Accepted November 6, 2016.
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