Research Department

Medical Oncology/Hematologic Neoplasia

Interest

Leukemia

Area of Research

Biography

Dr. Letai received his MD and PhD from the University of Chicago. He completed his residency in internal medicine at Brigham and Women's Hospital, and a fellowship in hematology and oncology at DFCI. He did his postdoctoral research training in the laboratory of Dr. Stanley Korsmeyer. Dr. Letai's research focuses on the mechanisms by which cancer cells evade death, and on the application of that knowledge to the selective killing of cancer cells. He joined the faculty of DFCI and Harvard Medical School in 2004.

Recent Awards

• American Society of Clinical Investigation, Elected Member, 2009
• Leukemia and Lymphoma Society Scholar Award, 2008
• Kimmel Scholar Award, 2005
• V Scholar Award, 2005
• Smith Family New Investigator, 2004

Research

The cells of the body are constructed so that if they become sufficiently damaged or abnormal, programmed cell death, or apoptosis, rapidly eliminates them before they can cause any harm. Cancer cells, which bear many abnormalities, apparently have found ways to escape this death sentence. One way that cancer cells escape death is via the overexpression of antideath proteins in the BCL-2 family. We are investigating how these antideath proteins might be selectively targeted in cancer cells.

Using a combination of mouse models, protein biochemistry, and mitochondrial and cellular studies, we have determined conditions under which cancer and normal cells are susceptible to inhibition of BCL-2 family function. We are collaborating with biotechnology and pharmaceutical firms to bring small-molecule BCL-2 antagonists to clinical trial here at Dana-Farber. Most likely, the novel strategy of BCL-2 antagonism will first be tested in chronic lymphocytic leukemia, small-cell lung cancer, and non-Hodgkin's lymphoma. If these trials are successful, the strategy of BCL-2 antagonism may find wide application in other human cancers.

We also investigate more fundamental questions about how interactions among BCL-2 family proteins govern death and survival in normal and cancer cells. We explore how these proteins participate in a wide range of death signals, growth factor withdrawal, and chemotherapy.

Select Publications

• Opferman JT, Letai A, Beard C, Sorcinelli M, Ong CC, Korsmeyer SJ. Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1. Nature 2003;426:671-6.
• Letai A, Sorcinelli M, Beard C, Korsmeyer SJ. Antiapoptotic BCL-2 is required for maintenance of a model leukemia. Cancer Cell 2004;6:241-9.
• Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, Hajduk PJ, Joseph MK, Kitada S, Korsmeyer SJ, Kunzer AR, Letai A, Li C, Mitten MJ, Nettesheim DG, Ng SC, Nimmer PM, O'Connor JM, Oleksijew A, Petros AM, Reed JC, Shen W, Tahir S, Thompson CB, Tomaselli KJ, Wang B, Wendt MD, Zhang H, Fesik SW, Rosenberg SH. An inhibitor of Bcl-2 family proteins induces regression of solid tumors. Nature 2005;435:677-81.
• Letai A. Pharmacologic manipulation of BCL-2 family members to control cell death. J Clin Invest 2005;115:2648-55.
• Letai A. BCL-2: found bound and drugged! Trends Mol Med 2005;11:442-4.
• Vo, T. T., Ryan, J., Carrasco, R., Neuberg, D., Rossi, D. J., Stone, R. M., Deangelo, D. J., Frattini, M. G. & Letai, A. Relative Mitochondrial Priming of Myeloblasts and Normal HSCs Determines Chemotherapeutic Success in AML. Cell 151, 344-355 (2012).
• Davids, M. S., Deng, J., Wiestner, A., Lannutti, B. J., Wang, L., Wu, C. J., Wilson, W. H., Brown, J. R. & Letai, A. Decreased mitochondrial apoptotic priming underlies stroma-mediated treatment resistance in chronic lymphocytic leukemia. Blood (2012).

Trainees

• Deng, Jing, Ph.D.
• Montero-Boronat, Joan, Ph.D.
• Guerriero, Jennifer, Ph.D.
• Bhola, Patrick, Ph.D.
• Chonghaile, Triona, Ph.D.
• Sarosiek, Patrick, Ph.D.
• Patel, Luv, M.S.
• Hogdal, Leah, B.S.