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 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 the leukemic stem cells of acute myeloid or acute lymphoid leukemia. We work to (i) identify genetic changes that contribute to leukemia, (ii) delineate how genetic changes combine at the cellular and molecular levels to cause transformation (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 RARalpha, can induce remission in patients with the PML/RARalpha fusion by stimulating the leukemic cells to differentiate into mature neutrophils. APL has become the most curable of the myeloid leukemias. Our hope is that this disorder may serve as a “Rosetta Stone” for understanding acute myeloid leukemia (AML) more generally; that by studying this disease and its response to treatment we will learn how to extend differentiation therapy to other AMLs. We utilize a mouse model of APL for many of our studies. By characterizing the leukemic stem cell in APL, which appears to be a relatively mature myeloid cell, we are gaining insight into the mechanisms governing abnormal persistence and self-renewal.
A related area of study is overcoming chemotherapy resistance in AML. Approximately 80% of children and adults less than 50 years old who are diagnosed with AML go into complete remission after induction chemotherapy. However, almost half of these patients relapse, and such relapsed disease is often resistant to treatment. Initial or acquired resistance to treatment is even more common in older adults as well as in secondary AMLs, an increasingly common illness in patients who have survived after treatment of for other malignancies. Hence, overcoming resistance to chemotherapy is a goal of great clinical import. By understanding the leukemic stem cells that give rise to relapse we should be able to better target these cells for treatment.
Another area of investigation is developing mouse models of pediatric acute lymphoblastic leukemia (pre-B ALL). A number of mouse models of AML based upon the genetic lesions present in human AML have been developed, but there are significant gaps in the availability of mouse models of pre-B ALL. Although 25% of pediatric pre-B ALL contains a t(12;21) translocation resulting in a fusion of two transcription factors, TEL-AML1, previous attempts to establish a mouse model of TEL-AML1 induced pre-B ALL have met with limited success. Such a model could be utilized to test hypotheses about pediatric pre-B ALL carcinogenesis (for example, the potential contribution to leukemogenesis of dietary factors or environmental exposures), pathogenesis (structure-function studies, cooperating events, stem cells), and treatment.