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.
Li, Q; Haigis, KM; McDaniel, A; Harding-Theobald, E; Kogan, SC; Akagi, K; Wong, JC; Braun BS; Wolff L; Jacks T; Shannon K. Hematopoiesis and leukemogenesis in mice expressing oncogenic NrasG12D from the endogenous locus. Blood, 2011, 117:2022-2032. PMCID: PMC3056645
Premsrirut, PK; Dow LE; Kim, SY; Camiolo, M; Malone, CD; Miething, C; Scuoppo, C; Zuber, J; Dickins, RA; Kogan, SC; Shroyer, KR; Sordella, R; Hannon, GJ; Lowe SW. A rapid and scalable system for studying gene function in mice using conditional RNA interference. Cell, 2011, 145:145-158. PMCID:PMC3244080
Zuber, J; Shi, J; Wang, E; Rappaport, AR; Herrmann, H; Sison, EA; Magoon, D; Qi, J; Blatt, K; Wunderlich, M; Taylor, MJ; Johns, C; Chicas, A; Mulloy, JC; Kogan, SC; Brown, P; Valent, P; Bradner, JE; Lowe, SW; Vakoc, CR. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature, 2011, 478:524-528. PMCID: PMC3328300
Wang X, Takagawa J, Lam VC, Haddad DJ, Tobler DL, Mok PY, Zhang Y, Clifford BT, Pinnamaneni K, Saini SA, Su R, Bartel MJ, Sievers RE, Carbone L, Kogan S, Yeghiazarians Y, Hermiston M, Springer ML. Donor myocardial infarction impairs the therapeutic potential of bone marrow cells by an interleukin-1-mediated inflammatory response. Sci Transl Med. 2011, 3:100ra90. PMCID:PMC3350804
Choi G, Huang B, Pinarbasi E, Braunstein SE, Horvai AE, Kogan S, Bhatia S, Faddegon B, Nakamura JL. Genetically mediated Nf1 loss in mice promotes diverse radiation-induced tumors modeling second malignant neoplasms. Cancer Res. 2012 72:6425-34. PMCID: PMC3787120.
Bergerson RJ, Collier LS, Sarver AL, Been RA, Lugthart S, Diers MD, Zuber J, Rappaport AR, Nixon MJ, Silverstein KA, Fan D, Lamblin AF, Wolff L, Kersey JH, Delwel R, Lowe SW, O'Sullivan MG, Kogan SC, Adams DJ, Largaespada DA. An insertional mutagenesis screen identifies genes that cooperate with Mll-AF9 in a murine leukemogenesis model. Blood. 2012, 119:4512-23. PMCID: PMC3362364.
Bagley BN, Keane TM, Maklakova VI, Marshall JG, Lester RA, Cancel MM, Paulsen AR, Bendzick LE, Been RA, Kogan SC, Cormier RT, Kendziorski C, Adams DJ, Collier LS. A dominantly acting murine allele of Mcm4 causes chromosomal abnormalities and promotes tumorigenesis. PLoS Genet. 2012;8:e1003034. PMCID: PMC3486839.
Omidvar N, Maunakea ML, Jones L, Sevcikova S, Yin B, Himmel KL, Tennant TR, LeBeau MM, Largaespada DA, Kogan SC. PML-RARalpha cooperates with SOX4 in acute myeloid leukemia development in mice. Haematologica 2013;98:424-7. PMCID:PMC3659942
Chang T, Krisman K, Theobald EH, Xu J, Akutagawa J, Lauchle JO, Kogan S, Braun BS, Shannon K. Sustained MEK inhibition abrogates myeloproliferative disease in Nf1 mutant mice. J Clin Invest. 2013, 123:335-9. PMCID: PMC3533281.
Li M, Jones L, Gaillard C, Binneweis M, Ochoa R, Garcia E, Lam V, Wei G, Yang W, Lobe C, Hermiston M, Passegué E, Kogan SC. Initially Disadvantaged, TEL-AML1 Cells Expand and Initiate Leukemia in Response to Irradiation and Cooperating Mutations. Leukemia 2013, 27:1570-3. PMCID:PMC3715751.
Smith CC, Lasater E, Lin K, Wang Q, McCreery MQ, Stewart W, Damon LE, Perl AE, Jeschke GR, Sugitad M, Carroll M, Kogan SC, Kuriyan J, Shah NP. Crenolanib is a selective type I pan-FLT3 inhibitor. Proc Natl Acad Sci USA 2014, 111:5319-24.PMCID: PMC3986131.
Chen C, Liu Y, Rappaport AR, Kitzing T, Schultz N, Zhao Z, Shroff AS, Dickins RA, Vakoc CR, Bradner JE, Stock W, LeBeau MM, Shannon KM, Kogan S, Zuber J, Lowe SW. MLL3 is a haploinsufficient 7q tumor suppressor in acute myeloid leukemia. Cancer Cell. 2014 25:652-65. PMCID: PMC4206212.