Raaijmakers Lab

1. Bone progenitor cells in the pathogenesis of myelodysplastic syndromes
Carcinogenesis in humans is a multistep process from a pre-malignant state towards frank malignancy. Myelodysplastic syndrome (MDS) is the most prevalent leukemia predisposition state in the hematopoietic system. The early events driving the initiation and leukemic evolution of this disorder have remained elusive. It was recently shown that dysfunction of bone progenitor cells (osteoprogenitors) in the bone marrow microenvironment induces myelodysplasia and secondary leukemia in mice1. The data reveal that primary changes in a tissue microenvironment can induce malignant transformation of heterotypic cell types, thus supporting a concept of niche-induced oncogenesis. The findings raise the prospect of niche-targeted strategies in the treatment and prevention of leukemia. In this project, we aim to obtain further insights into the molecular crosstalk between osteoprogenitor and hematopoietic cells governing myelodysplasia and leukemogenesis and test its relevance for human disease.

2. Targeting the niche in Shwachman-Diamond syndrome
The Shwachman-Diamond Syndrome (SDS) is a rare autosomal recessive multisystemic disorder. It is typically diagnosed in early childhood and characterized by bone marrow failure (neutropenia and pancytopenia) and the propensity to develop acute myeloid leukemia. The vast majority of SDS patients have loss-of function mutations in the Shwachman-Bodian Diamond Syndrome (SBDS) gene, encoding a protein with pleiotropic function involved in ribosome biogenesis. How dysfunction of SBDS or ribosomal proteins causes the propensity to develop bone marrow falure and leukemia is poorly understood. It was recently demonstrated that targeted deletion of Sbds from bone progenitor cells induces disruption of hematopiesis, recapitulating important characteristics of human SDS1.
In this project we will test the hypothesis that specific molecular abnormalities in osteoprogenitor cells cooperate with hematopoietic cells in the pathogenesis of human SDS. We will also test whether osteoprogenitor cell transplantation is a feasible therapeutic modality in this disease in preclinical models. Insight into the pathogenesis of this rare disease is of great importance not only because this will lead to more effective and safer treatment strategies for young patients with this severe disease, but also because this disorders provides a unique possibility to study early events in carcinogenesis and leukemogenesis.

1Raaijmakers M, Mukherjee S, Guo S, Kobayashi T, Zhang S, Schoonmaker J, Ebert B, Lin C,  Rommens J, Scadden D. Osteoprogenitor cell dysfunction induces myelodysplasia and secondary leukemia. Nature 2010;8;464(7290):852-7.