Stromal Interactions and Leukemic Risk in Myelodysplastic Syndromes

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 DESCRIPTION (provided by applicant): Myelodysplastic syndromes (MDS) comprise a group of hematopoietic stem cell disorders that have been etiologically linked to exposure to carcinogens and evolve into acute myeloid leukemia (AML) in approximately 30% of cases. Bone marrow fibrosis is an inflammatory stromal reaction that substantially reduces leukemia-free survival of MDS patients. However, the mechanisms that accelerate AML evolution in patients who have MDS with fibrosis are poorly understood. Treatment of MDS when fibrosis is minimal greatly improves outcomes, but there are no molecular tools for distinguishing this disease at its early stage from other hematologic disorders that have similar morphologic features. Homeobox genes encode transcription factors that control cell lineage-specification and are aberrantly expressed in many types of tumors and pre-neoplastic lesions. In recent studies, we have identified that several homeobox genes promote tumorigenesis by deregulating a variety of signaling pathways that control tumor-stroma interactions. DLX4 is a homeobox gene that has been reported to be induced by carcinogen exposure and to be frequently overexpressed in AML. Our broad hypothesis is that DLX4 accelerates AML evolution in patients who have MDS with fibrosis by stimulating inflammatory signaling. In Aim 1, we will evaluate whether DLX4 expression in hematopoietic progenitor cells stimulates inflammatory signaling, induces MDS with fibrosis, and leads to AML evolution in mouse engraftment models. In Aim 2, we will evaluate the relationship between DLX4 expression, inflammatory signaling, fibrosis and AML evolution in a retrospective study of clinical specimens of MDS. If our study is successful, DLX4 could be a potential biomarker for distinguishing early-stage MDS with fibrosis from other morphologically similar diseases that have low risks of AML evolution. With our multi-disciplinary team of experts in homeobox genes, hematopathology and clinical management of MDS, this study will provide valuable insights into the molecular pathogenesis of MDS and its propensity for AML evolution.