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
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 : 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 : 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.
Bertoli Sarah, Picard Muriel, Bérard Emilie, Griessinger Emmanuel, Larrue Clément, Mouchel Pierre-Luc, Vergez François, Tavitian Suzanne, Yon Edwige, Ruiz Jean, Delabesse Eric, Luquet Isabelle, Linares Laetitia Karine, Saland Estelle, Carroll Martin, Danet-Desnoyers Gwenn, Sarry Audrey, Huguet Françoise, Sarry Jean-Emmanuel, Récher Christian: Dexamethasone in hyperleukocytic acute myeloid leukemia. Haematologica : 2018.
Vu Ly P, Pickering Brian F, Cheng Yuanming, Zaccara Sara, Nguyen Diu, Minuesa Gerard, Chou Timothy, Chow Arthur, Saletore Yogesh, MacKay Matthew, Schulman Jessica, Famulare Christopher, Patel Minal, Klimek Virginia M, Garrett-Bakelman Francine E, Melnick Ari, Carroll Martin, Mason Christopher E, Jaffrey Samie R, Kharas Michael G: The N(6)-methyladenosine (m(6)A)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells. Nature medicine 23 (11): 1369-1376,2017.
Farge Thomas, Saland Estelle, de Toni Fabienne, Aroua Nesrine, Hosseini Moshen, Perry Robin, Bosc Claudie, Sugita Mayumi, Stuani Lucille, Fraisse Marine, Scotland Sarah, Larrue Clément, Boutzen Héléna, Féliu Virginie, Nicolau-Travers Marie-Laure, Cassant-Sourdy Stephanie, Broin Nicolas, David Marion, Serhan Nizar, Sarry Audrey, Tavitian Suzanne, Kaoma Tony, Vallar Laurent, Iacovoni Jason, Linares Laetitia K, Montersino Camille, Castellano Remy, Griessinger Emmanuel, Collette Yves, Duchamp Olivier: Chemotherapy Resistant Human Acute Myeloid Leukemia Cells are Not Enriched for Leukemic Stem Cells but Require Oxidative Metabolism. Cancer discovery 7 (7): 716-735,2017.
Nabel Christopher S, DeNizio Jamie E, Carroll Martin, Kohli Rahul M: DNA Methyltransferases Demonstrate Reduced Activity against Arabinosylcytosine: Implications for Epigenetic Instability in Acute Myeloid Leukemia. Biochemistry 56 (16): 2166-2169,2017.
Tasian Sarah K, Kenderian Saad S, Shen Feng, Ruella Marco, Shestova Olga, Kozlowski Miroslaw, Li Yong, Schrank-Hacker April, Morrissette Jennifer J D, Carroll Martin, June Carl H, Grupp Stephan A, Gill Saar: Optimized Depletion of Chimeric Antigen Receptor T-Cells in Murine Xenograft Models of Human Acute Myeloid Leukemia. Blood : 2017.
Chung Stephen S, Eng William S, Hu Wenhuo, Khalaj Mona, Garrett-Bakelman Francine E, Tavakkoli Montreh, Levine Ross L, Carroll Martin, Klimek Virginia M, Melnick Ari M, Park Christopher Y: CD99 is a therapeutic target on disease stem cells in myeloid malignancies. Science translational medicine 9 (374): 2017.
Wertheim Gerald B W, Luskin Marlise R, Carroll Martin, Master Stephen R: Microsphere-Based Assessment of DNA Methylation for AML Prognosis. Methods in molecular biology (Clifton, N.J.) 1633 : 125-136,2017.
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