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

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 CD34CD38 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.

Revisiting CLEC12A as leukaemic stem cell marker in AML: highlighting the necessity of precision diagnostics in patients eligible for targeted therapy

“…As exemplified in AML 3, this variation in VAFs may uncover the clonal heterogeneity and hierarchical leukaemic evolution of the different subclones (Fig ). In addition, the finding of pre‐leukaemic mutations in some of the LTC‐IC derived colonies supports previous reports of pronounced functional heterogeneity of genetically different subclones (Klco et al , ; Chesnais et al , ).…”

“…However, we confirmed the findings of previous studies, showing a preponderance of LTC‐IC activity in cells with early leukaemogenic events, e.g. in epigenetic or chromatin modifying genes, such as TET2 and ASXL1 (Chesnais et al , ). In addition, the data from targeted NGS on highly purified cell subsets strongly suggested a hierarchical relationship between the ALDH br CD34+CLEC12A− and ALDH br CLEC12A+ cell subsets, indicating that the pre‐leukaemic and/or founding clones often arise in the most immature ALDH br CD34+CLEC12A− cells with additional driver mutations emerging either in a ALDH br CD34+CLEC12A− cell or in a more mature ALDH br CLEC12A+ cell.…”

“…Current literature suggests these particular cells to possess stem cell properties in terms of quiescence, self‐renewal capacity and an increased resistance to chemotherapy (Griessinger et al , ), and LSCs are thought to be responsible for relapse in the vast majority of AML patients (Bonnet, ). It is noteworthy that, while the identification of recurrently mutated genes in AML has expanded our view of AML pathophysiology (Cancer Genome Atlas Research Network et al , ), studies integrating knowledge of the mutational architecture with the hierarchical cancer stem cell model are sparse (Klco et al , ; Chesnais et al , ). Thus, LSCs are attractive targets in the development of new treatment modalities in AML (Bruserud et al , ), and a precise and in‐depth characterization of these cells, including an understanding of how they differ from their normal counterparts, is essential.…”

Single-Cell Omics Analyses Enabled by Microchip Technologies

“…Genetic mutations and variations can be inherited or arise during cell proliferation and differentiation, ultimately resulting in genotypic heterogeneity (26)(27)(28)(29). Through whole-genome sequencing, the mutations, structural variations, aneuploidies, and recombination in the genome can be characterized (30)(31)(32)(33)(34)(35)(36).…”

Mechanisms underlying the heterogeneity of myelodysplastic syndromes

“…In this case, the dominant SF3B1mutated clone of the hematopoietic stem/progenitor cell (HSPC) compartment gives an SF3B1-mutated progeny of myeloid and lymphoid cells in xenograft experiments. In contrast, when the mutation SF3B1 occurs after the epigenetic event, and even if SF3B1 mutation belongs to a dominant clone, it appears as a minor myeloid clone in mouse bone marrow [27]. The companion mutations in the different clones may influence engraftment capacities and cooperate with the initiating events to propagate the disease.…”