Molecular biology of leukemia
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
Leukemia and myelodysplastic syndromes
Luskin Marlise R, Carroll Martin, Lieberman David, Morrissette Jennifer J D, Zhao Jianhua, Crisalli Lisa, Roth David B, Luger Selina M, Porter David L, Reshef Ran: Clinical Utility of Next-Generation Sequencing for Oncogenic Mutations in Patients with Acute Myeloid Leukemia Undergoing Allogeneic Stem Cell Transplantation. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation Jul 2016.
Li Sheng, Garrett-Bakelman Francine E, Chung Stephen S, Sanders Mathijs A, Hricik Todd, Rapaport Franck, Patel Jay, Dillon Richard, Vijay Priyanka, Brown Anna L, Perl Alexander E, Cannon Joy, Bullinger Lars, Luger Selina, Becker Michael, Lewis Ian D, To Luen Bik, Delwel Ruud, Löwenberg Bob, Döhner Hartmut, Döhner Konstanze, Guzman Monica L, Hassane Duane C, Roboz Gail J, Grimwade David, Valk Peter J M, D'Andrea Richard J, Carroll Martin, Park Christopher Y, Neuberg Donna, Levine Ross, Melnick Ari M, Mason Christopher E: Distinct evolution and dynamics of epigenetic and genetic heterogeneity in acute myeloid leukemia. Nature medicine 22(7): 792-9, Jul 2016.
Luskin Marlise R, Gimotty Phyllis A, Smith Catherine, Loren Alison W, Figueroa Maria E, Harrison Jenna, Sun Zhuoxin, Tallman Martin S, Paietta Elisabeth M, Litzow Mark R, Melnick Ari M, Levine Ross L, Fernandez Hugo F, Luger Selina M, Carroll Martin, Master Stephen R, Wertheim Gerald B W: A clinical measure of DNA methylation predicts outcome in de novo acute myeloid leukemia. JCI insight 1(9), Jun 2016.
Sloan Caroline E, Luskin Marlise R, Boccuti Anne M, Sehgal Alison R, Zhao Jianhua, Daber Robert D, Morrissette Jennifer J D, Luger Selina M, Bagg Adam, Gimotty Phyllis A, Carroll Martin: A Modified Integrated Genetic Model for Risk Prediction in Younger Patients with Acute Myeloid Leukemia. PloS one 11(4): e0153016, 2016.
Nybakken G E, Canaani J, Roy D, Morrissette J D, Watt C D, Shah N P, Smith C C, Bagg A, Carroll M, Perl A E: Quizartinib elicits differential responses that correlate with karyotype and genotype of the leukemic clone. Leukemia 30(6): 1422-5, Nov 2015.
Paguirigan Amy L, Smith Jordan, Meshinchi Soheil, Carroll Martin, Maley Carlo, Radich Jerald P: Single-cell genotyping demonstrates complex clonal diversity in acute myeloid leukemia. Science translational medicine 7(281): 281re2, Apr 2015.
Sehgal Alison R, Gimotty Phyllis A, Zhao Jianhua, Hsu Jing-Mei, Daber Robert, Morrissette Jennifer D, Luger Selina, Loren Alison W, Carroll Martin: DNMT3A Mutational Status Affects the Results of Dose-Escalated Induction Therapy in Acute Myelogenous Leukemia. Clinical cancer research : an official journal of the American Association for Cancer Research 21(7): 1614-20, Apr 2015.
Kenderian S S, Ruella M, Shestova O, Klichinsky M, Aikawa V, Morrissette J J D, Scholler J, Song D, Porter D L, Carroll M, June C H, Gill S: CD33 Specific Chimeric Antigen Receptor T Cells Exhibit Potent Preclinical Activity against Human Acute Myeloid Leukemia. Leukemia Feb 2015.
Kalota Anna, Selak Mary A, Garcia-Cid Laura A, Carroll Martin: Eltrombopag modulates reactive oxygen species and decreases acute myeloid leukemia cell survival. PloS one 10(4): e0126691, 2015.
Wertheim Gerald B W, Smith Catherine, Luskin Marlise, Rager Alison, Figueroa Maria E, Carroll Martin, Master Stephen R: Validation of DNA Methylation to Predict Outcome in Acute Myeloid Leukemia by Use of xMELP. Clinical chemistry 61(1): 249-58, Oct 2014.
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Last updated: 10/03/2016
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