Description of Research Expertise:
Molecular biology of leukemia
Key words: Leukemia, BCR/ABL, signal transduction, PI3 kinase.
Description of Research
My laboratory is broadly interested in the molecular biology of leukemia. There are two active areas of research in the laboratory. The first project focused on acute myeloid leukemia (AML). AML has been hypothesized to arise from a combination of oncogenic translocations that disrupt cellular disruption and dysregulation of cellular growth regulatory mechanisms. Although a number of translocations are identified which block differentiation in AML cells, the mechanism of increased cell growth is poorly understood. We are working to understand the signal transduction pathways activated in primary cells from patients with acute myeloid leukemia (AML). We have recently found that over 80% of AML patient samples have activation of the PI3 kinase signaling pathway and that these cells require activation of the PI3 kinase pathway for survival. We are continuing to work on the PI3 kinase pathway in these primary patient cells in order to determine the exact role of the pathway in AML. Experiments are in progress to test the use of PI3 kinase pathway inhibitors in the therapy of AML using a NOD/SCID xenograft model of the disease. We are also working to develop improved culture conditions for primary AML cells in order to define the growth regulatory pathways that maintain the survival of these cells in patients.
A second project involves the role of genomic instability in progression of chronic myeloid leukemia (CML) from the chronic phase to the terminal blast crisis phase of disease. CML arises because of the t(9;22) translocation which gives rise to the BCR/ABL oncogene. Extensive work has shown that BCR/ABL is a constitutively activated tyrosine kinase that leads to constitutive activation of signal transduction pathways in leukemic cells causing their aberrant growth. However, the role of BCR/ABL in progression to blast crisis is unknown. We have recently demonstrated that BCR/ABL alters the cellular response to DNA damage. After DNA damage, BCR/ABL translocates from the cytoplasm to the nucleus. In the nucleus, the oncogene associates with and disrupts the function of the ataxia-telangiectasia and rad 3 related (ATR) protein which regulates cell cycle checkpoints and DNA repair. We are actively working on trying to define the mechanism of translocation and association with ATR in order to better understand the role of BCR/ABL in progression of this disease.
1. Understanding the effects of hypoxia on growth of MDS cells.
2. Defining targets of mTOR signaling in AML.
3. Effects of BCR/ABL on genomic instability.
Jamil Dierov PhD, DS. - Staff Scientist
James Thompson, M.D. - Research Associate
Patty Sanchez, Ph.D. - Postdoctoral Fellow
Xiiowei Yang, Ph.D. - Postdoctoral Fellow
Beth Burke - Graduate Student
Kristin Brennan - Research Specialist
McMahon Christine M, Canaani Jonathan, Rea Bryan, Sargent Rachel L, Qualtieri Julianne N, Watt Christopher D, Morrissette Jennifer J D, Carroll Martin, Perl Alexander E: Gilteritinib induces differentiation in relapsed and refractory -mutated acute myeloid leukemia. Blood advances 3 (10): 1581-1585,2019.
Duy Cihangir, Teater Matt, Garrett-Bakelman Francine E, Lee Tak C, Meydan Cem, Glass Jacob L, Li Meng, Hellmuth Johannes C, Mohammad Helai P, Smitheman Kimberly N, Shih Alan H, Abdel-Wahab Omar, Tallman Martin S, Guzman Monica L, Muench David, Grimes H Leighton, Roboz Gail J, Kruger Ryan G, Creasy Caretha L, Paietta Elisabeth M, Levine Ross L, Carroll Martin, Melnick Ari M: Rational Targeting of Cooperating Layers of the Epigenome Yields Enhanced Therapeutic Efficacy against AML. Cancer discovery : 2019.
McMahon Christine M, Ferng Timothy, Canaani Jonathan, Wang Eunice S, Morrissette Jennifer Jd, Eastburn Dennis J, Pellegrino Maurizio, Durruthy-Durruthy Robert, Watt Christopher D, Asthana Saurabh, Lasater Elisabeth A, DeFilippis RosaAnna, Peretz Cheryl A C, McGary Lisa H F, Deihimi Safoora, Logan Aaron C, Luger Selina M, Shah Neil P, Carroll Martin, Smith Catherine C, Perl Alexander E: Clonal selection with Ras pathway activation mediates secondary clinical resistance to selective FLT3 inhibition in acute myeloid leukemia. Cancer discovery : 2019.
Sung Pamela J, Sugita Mayumi, Koblish Holly, Perl Alexander E, Carroll Martin: Hematopoietic cytokines mediate resistance to targeted therapy in FLT3-ITD acute myeloid leukemia. Blood advances 3 (7): 1061-1072,2019.
Black Kathryn L, Naqvi Ammar S, Asnani Mukta, Hayer Katharina E, Yang Scarlett Y, Gillespie Elisabeth, Bagashev Asen, Pillai Vinodh, Tasian Sarah K, Gazzara Matthew R, Carroll Martin, Taylor Deanne, Lynch Kristen W, Barash Yoseph, Thomas-Tikhonenko Andrei: Aberrant splicing in B-cell acute lymphoblastic leukemia. Nucleic acids research 47 (2): 1043,2019.
Litzow Mark R, Wang Xin V, Carroll Martin P, Karp Judith E, Ketterling Rhett P, Zhang Yanming, Kaufmann Scott H, Lazarus Hillard M, Luger Selina M, Paietta Elisabeth M, Pratz Keith W, Tun Han Win, Altman Jessica K, Broun Edward R, Rybka Witold B, Rowe Jacob M, Tallman Martin S: A randomized trial of three novel regimens for recurrent acute myeloid leukemia demonstrates the continuing challenge of treating this difficult disease. American journal of hematology 94 (1): 111-117,2019.
Urtishak Karen A, Wang Li-San, Culjkovic-Kraljacic Biljana, Davenport James W, Porazzi Patrizia, Vincent Tiffaney L, Teachey David T, Tasian Sarah K, Moore Jonni S, Seif Alix E, Jin Shenghao, Barrett Jeffrey S, Robinson Blaine W, Chen I-Ming L, Harvey Richard C, Carroll Martin P, Carroll Andrew J, Heerema Nyla A, Devidas Meenakshi, Dreyer ZoAnn E, Hilden Joanne M, Hunger Stephen P, Willman Cheryl L, Borden Katherine L B, Felix Carolyn A: Targeting EIF4E signaling with ribavirin in infant acute lymphoblastic leukemia. Oncogene 38 (13): 2241-2262,2018.
Schwartz Gregory W, Manning Bryan S, Zhou Yeqiao, Velu Priya D, Bigdeli Ashkan, Astles Rachel, Lehman Anne W, Morrissette Jennifer Jd, Perl Alexander E, Li Mingyao, Carroll Martin, Faryabi Robert Babak: Classes of ITD predict outcomes in AML patients treated with FLT3 inhibitors. Clinical cancer research : an official journal of the American Association for Cancer Research 25 (2): 573-583,2018.
Kasner Margaret T, Mick Rosemarie, Jeschke Grace R, Carabasi Matthew, Filicko-O'Hara Joanne, Flomenberg Neal, Frey Noelle V, Hexner Elizabeth O, Luger Selina M, Loren Alison W, Mangan James K, Wagner John L, Weiss Mark, Carroll Martin, Perl Alexander E: Sirolimus enhances remission induction in patients with high risk acute myeloid leukemia and mTORC1 target inhibition. Investigational new drugs 36 (4): 657-666,2018.
Krevvata Maria, Shan Xiaochuan, Zhou Chenghui, Dos Santos Cedric, Habineza Ndikuyeze Georges, Secreto Anthony, Glover Joshua, Trotman Winifred, Brake-Silla Gisela, Nunez-Cruz Selene, Wertheim Gerald, Ra Hyun-Jeong, Griffiths Elizabeth, Papachristou Charalampos, Danet-Desnoyers Gwenn, Carroll Martin: Cytokines increase engraftment of human acute myeloid leukemia cells in immunocompromised mice but not engraftment of human myelodysplastic syndrome cells. Haematologica : 2018.
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