Immunology Faculty Member - Alejandro Gutierrez, PhD

Alejandro, MD

Boston Children's Hospital
300 Longwood Avenue, Karp 8

Boston, MA 02115
Tel: 617-919-3660
Fax: 617-730-0934
Visit my lab page here.

The overarching focus of our laboratory is to unravel the molecular pathogenesis of high-risk T-cell acute lymphoblastic leukemia (T-ALL). Specifically, we aim to define the molecular mechanisms responsible for resistance to conventional chemotherapy, and to develop novel effective therapies for these patients. Our approach combines genomic and biochemical studies in primary patient samples, together with mechanistic studies in genetically engineered zebrafish and mouse model systems.

A major focus of the lab is mechanisms of resistance to mitochondrial apoptosis in T-ALL. Conventional chemotherapy cures patients when it effectively kills cancer cells, and we have now shown that treatment-resistant T-ALL is characterized by innate resistance to mitochondrial apoptosis. The mechanisms underlying apoptosis resistance in these cases are unknown. We have found a link between apoptosis resistance and mutations of specific pathways with key roles during normal T-cell development, but whose contributions to T-ALL pathobiology are poorly understood. Our current focus lies in unraveling the molecular link between these developmental signaling pathways and the mitochondrial apoptotic machinery, and on devising rational strategies for therapeutic intervention.

A second focus of the lab is the application of unbiased screens for discovery of novel therapeutic strategies. Using a zebrafish drug screen, we found that perphenazine, an FDA-approved antipsychotic, effectively kills T-ALL cells. However, its molecular target was unrelated to any of its known biologic targets. Using a proteomics approach, we showed that perphenazine kills T-ALL cells by directly binding and activating the PP2A phosphatase. Our interests are to define the structural basis of PP2A activation by perphenazine, and develop more potent and specific PP2A activators. More broadly, we are interested in applying novel models for such drug discovery efforts.

Last Update: 10/15/2015


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