Journal Article

Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia

Aung, Zinmar, Hasserjian, Robert P., Merkenschlager, Matthias, Matza, Marc, Guo, Shangqin, Ebert, Benjamin L., Zhang, Siyi, Scadden, David. T., Scadden, Edward O., Mukherjee, Siddhartha, Kobayashi, Tatsuya, Al-Shahrour, Fatima, Rommens, Johanna M., Lin, Charles, Raaijmakers, Marc H. G. P., Schoonmaker, Jesse A.

2010

Overview

Mesenchymal cells contribute to the ‘stroma’ of most normal and malignant tissues, with specific mesenchymal cells participating in the regulatory niches of stem cells. By examining how mesenchymal osteolineage cells modulate haematopoiesis, here we show that deletion of Dicer1 specifically in mouse osteoprogenitors, but not in mature osteoblasts, disrupts the integrity of haematopoiesis. Myelodysplasia resulted and acute myelogenous leukaemia emerged that had acquired several genetic abnormalities while having intact Dicer1 . Examining gene expression altered in osteoprogenitors as a result of Dicer1 deletion showed reduced expression of Sbds , the gene mutated in Schwachman–Bodian–Diamond syndrome—a human bone marrow failure and leukaemia pre-disposition condition. Deletion of Sbds in mouse osteoprogenitors induced bone marrow dysfunction with myelodysplasia. Therefore, perturbation of specific mesenchymal subsets of stromal cells can disorder differentiation, proliferation and apoptosis of heterologous cells, and disrupt tissue homeostasis. Furthermore, primary stromal dysfunction can result in secondary neoplastic disease, supporting the concept of niche-induced oncogenesis. The cancer cell niche Although a series of genetic and epigenetic events in a single cell may be necessary for oncogenesis, it has been suggested that for malignancy to develop fully a permissive microenvironment or niche is required. Support for this view comes from a new mouse model in which haematopoietic malignancies are caused by genetic changes in the microenvironment of blood cells. Deletion in bone progenitor cells of Dicer1 , a gene involved in microRNA processing, leads to a myelodysplastic syndrome-like phenotype that can progress to leukaemia. The progenitor cells have reduced levels of Sbds , the gene mutated in Schwachman–Bodian–Diamond syndrome, a bone marrow failure that predisposes to leukaemia. A new mouse model is developed in which haematopoietic malignancies are caused by genetic changes in the microenvironment of blood cells. Deletion in bone progenitor cells of Dicer1 , a gene involved in microRNA processing, leads to a myelodysplastic syndrome-like phenotype which can progress to leukaemia. Deregulation of Sbds , which is mutated in human Schwachman–Bodian–Diamond syndrome, may be involved in this process.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 692/698/233/1343 / 692/699/1541 / 692/699/67/1990/283 / Animal tumors. Experimental tumors / Animals / Apoptosis / Biological and medical sciences / Bone and Bones - metabolism / Bone and Bones - pathology / Bone marrow / Bone Marrow - metabolism / Bone Marrow - pathology / Cell Differentiation / Cell Lineage / Development and progression / Dysplasia / Experimental malignant blood diseases / Female / Gene Deletion / Genetic abnormalities / Genetic aspects / Health aspects / Hematopoiesis - genetics / Humanities and Social Sciences / Leukemia / Leukemia, Myeloid, Acute - genetics / Leukemia, Myeloid, Acute - metabolism / Leukemia, Myeloid, Acute - pathology / Male / Medical sciences / Mesoderm - cytology / Mice / Mortality / multidisciplinary / Myelodysplastic Syndromes - genetics / Myelodysplastic Syndromes - metabolism / Myelodysplastic Syndromes - pathology / Osteoblasts - metabolism / Osteoblasts - pathology / Phenotype / Proteins - genetics / Proteins - metabolism / Ribonuclease III - deficiency / Ribonuclease III - genetics / Ribonuclease III - metabolism / Risk factors / Sarcoma, Myeloid - genetics / Sarcoma, Myeloid - metabolism / Sarcoma, Myeloid - pathology / Science / Stem Cell Niche - metabolism / Stem Cell Niche - pathology / Stem cells / Stem Cells - metabolism / Stem Cells - pathology / Stromal Cells - metabolism / Stromal Cells - pathology / Studies / Tumors