Acute lymphoblastic leukemia (ALL) is a cancer originating from blood cells that proliferate in the bone marrow. ALL represents the most frequent pediatric leukemia, making up about a third of all childhood cancers. Gradual improvement in treatments have led to better survival rates. However, patients with ALL who fail to achieve complete remission or those whose disease relapses have very poor outcomes. A better understanding of the molecular events underlying leukemia, will be needed to develop specific and more effective antileukemic drugs.
During leukemia development, abnormal blood cells accumulate mutations in their DNA that dysregulate important cellular processes that enhance survival and proliferation of cancer cells. In addition to mutations to the DNA, epigenetic changes, which are heritable changes that do not involve direct modifications of the DNA sequence, have a clear functional impact on cancer development. Temporal and spatial gene transcriptional regulation of cellular states during development is coordinated by clusters of regulatory enhancers organized in regulatory domains. These enhancers regulate gene transcription through changes in DNA binding activity of proteins as well as epigenetic changes. We hypothesize that oncogenic genetic drivers and mutations in T-ALL alter the regulatory logic controlling chromatin accessibility of developmental enhancers active in early thymocytes locking T-ALL lymphoblasts in a hyperproliferative and differentiation-arrested developmental state. This opens a new therapeutic window for cancer treatment.
We are studying the epigenetic dysregulation of T cell acute lymphoblastic leukemia (T-ALL). By using innovative technologies and primary patient samples, we will study the functional relevance of chromatin accessibility gene regulatory enhancers, providing a high-resolution map of the active (open) and inactive (closed) regions of the genome. The comparison of this oncogenic map with normal healthy cells will highlight the regions that change their functionality in leukemia. For the first time we will elaborate a complete map of the regulatory functions of the genome in T-ALL, defining active as well as inactive genes as well as areas with no expression that function to enhance the expression of other genes. This study will also elucidate the strategies of oncogenic activation of these DNA regions, the proteins involved in these pathways and the dependency of leukemic cells on these dysregulated processes. This may eventually lead to therapeutic strategies to target these processes.
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