Scott Kogan, MD

Pathogenesis of Acute Leukemias

The broad long-term objective of work in the Kogan laboratory is to understand the pathogenesis of acute leukemias and to apply this understanding to prevent disease and to extend survival for patients with leukemias and other malignancies. Our scientific focus is to comprehend the alterations in cell fate decisions that govern the transformation of normal hematopoietic cells into acute myeloid or acute lymphoid leukemia. We work to (i) identify molecular changes that contribute to leukemia, (ii) delineate how genetic changes combine at the cellular and molecular levels to cause transformation and (iii) develop improved treatments using molecularly targeted therapeutics.

One major area of study is acute promyelocytic leukemia (APL). The recurrent chromosomal translocation, t(15;17)(q22;q12), is characteristic of APL. This translocation fuses the retinoic acid receptor alpha gene (RARA), a member of the nuclear steroid-thyroid hormone receptor superfamily, with the gene encoding PML, a nuclear protein that regulates cell growth and survival. Remarkably, all-trans retinoic acid, a ligand for RARα, along with arsenic trioxide, can induce remissions and the combination of these two agents results in cure in many patients. APL may therefore provide key information for developing effective treatments for other types of AML. Current specific projects include: (i) identifying mechanisms by which PML-RARα contributes to leukemia and response to ATRA and Arsenic therapy, (ii) characterizing the myeloid cells that serve as leukemic stem cells (LSC) in APL and identifying mechanisms by which the proliferative potential of these cells is expanded, and (iii) illuminating how two common genetic changes in human APL, activation of the FLT3 receptor tyrosine kinase and gain of chromosome 8, cooperate with PML-RARα in leukemic transformation.

A related area of study is delineating how normal myeloid cells exit the cell cycle. Whereas leukemic cells can proliferate indefinitely, normal myeloid progenitors and precursors have a very limited ability to divide. We developed an in vitro assay with which to identify genes that can permit additional cell divisions in myeloid development. We have used this assay to screen an shRNA library, and are currently evaluating candidate loci for their role in myelopoiesis.

An additional area of investigation is in mouse models of acute lymphoblastic leukemia (pre-B ALL). Although about 1 in 100 children are born with genetic changes in blood cells that are associated with leukemia, only about 1 in 10,000 develops ALL. Animal models could be useful for understanding why some children but not others develop ALL, but a mouse model of the most common form of pediatric pre-B ALL has been lacking. 25% of pediatric pre-B ALL contains a t(12;21) translocation resulting in a fusion of two transcription factors, TEL-AML1. Attempts to establish a mouse model of TEL-AML1 associated pre-B ALL had not yielded a robust model. We have worked to develop such a model and recent preliminary data suggest success in this endeavor. A number of factors have been implicated in increased risk of childhood ALL, including exposure to infections and environmental toxins. With a new model in hand, we are beginning to investigate how environmental influences (carcinogens, nutrition, infections) can protect from or accelerate the onset of disease in an animal model.

An area of ongoing interest is the characterization of hematopoiesis and neoplasia in genetically engineered mice. Dr. Kogan and his laboratory contribute to research projects of investigators locally, nationally, and internationally.