Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia

Abstract

Mesenchymal cell populations contribute to microenvironments regulating stem cells and the growth of malignant cells. Osteolineage cells participate in the hematopoietic stem cell niche. Here, we report that deletion of the miRNA processing endonuclease Dicer1 selectively in mesenchymal osteoprogenitors induces markedly disordered hematopoiesis. Hematopoietic changes affected multiple lineages recapitulating key features of human myelodysplastic syndrome (MDS) including the development of acute myelogenous leukemia. These changes were microenvironment dependent and induced by specific cells in the osteolineage. Dicer1−/− osteoprogenitors expressed reduced levels of Sbds, the gene mutated in the human bone marrow failure and leukemia predisposition Shwachman-Bodian-Diamond Syndrome. Deletion of Sbds in osteoprogenitors largely phenocopied Dicer1 deletion. These data demonstrate that differentiation stage-specific perturbations in osteolineage cells can induce complex hematological disorders and indicate the central role individual cellular elements of ‘estroma’ can play in tissue homeostasis. They reveal that primary changes in the hematopoietic microenvironment can initiate secondary neoplastic disease.

Secondary peripheral chondrosarcoma evolving from osteochondroma as a result of outgrowth of cells with functional EXT

“…In myelodysplasia and secondary leukemia, a 'nichebased' model of oncogenesis has been described, in which a change in a specific niche/microenvironmental cell can serve as the primary moment in a multi-step process toward the malignancy of a supported, but distinct, cell type (Raaijmakers et al, 2010;Raaijmakers, 2011). This model of oncogenesis seems to explain the formation of a secondary peripheral chondrosarcoma.…”

Les cellules souches mésenchymateuses

“…De plus, on ne peut exclure que des altérations géniques de CSM puissent favoriser le développement de certains cancers comme cela a été suggéré pour les cellules stromales composant la niche hématopoïétique dans le cas de certaines leucémies [30][31][32]. Ce champ d'investigation très actif aujourd'hui permettra d'envisager les potentialités et les écueils de l'utilisation des CSM dans le traitement des cancers, mais aussi le rôle des CSM endogènes dans le développement tumoral.…”

Deciphering the Key Features of Malignant Tumor Microenvironment for Anti-cancer Therapy

“…However, stromal cells with genetic and epigenetic abnormalities primarily induce the generation of CSCs and the development of malignant tumors [13]. Targeted deletion of Dicer1, the "landscape-modifying" miRNAprocessing endonuclease in osteoprogenitor cells, causes a myelodysplastic syndrome (MDS) in knockout mice, and the Dicer1-deleted mice develop acute myelogenous leukemia [13,92]. These abnormalities are dependent on the type of stromal cells in the microenvironment, because MDS was not observed when Dicer1 was deleted from mature osteoblasts.…”