Description of Research Expertise

Research Interests
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.

Rotation Projects
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.

Lab personnel:
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

Selected Publications

Skuli S, Matthews A, Carroll M, Lai C.: A line in shifting sand: Can we define and target TP53 mutated MDS? Semin Hematol : 2024.

Bowman RL, Dunbar AJ, Mishra T, Xiao W, Waarts MR, Maestre IF, Eisman SE, Cai L, Mowla S, Shah N, Youn A, Bennett L, Fontenard S, Gounder S, Gandhi A, Bowman M, O'Connor K, Zaroogian Z, Sánchez-Vela P, Martinez Benitez AR, Werewski M, Park Y, Csete IS, Krishnan A, Lee D, Boorady N, Potts CR, Jenkins MT, Cai SF, Carroll MP, Meyer SE, Miles LA, Ferrell PB Jr, Trowbridge JJ, Levine RL.: In vivo models of subclonal oncogenesis and dependency in hematopoietic malignancy Cancer Cell 42 : 1955-1969,2024.

Brown FC, Wang X, Birkinshaw RW, Chua CC, Morley TD, Kasapgil S, Pomilio G, Blombery P, Huang DCS Professor, Czabotar PE, Priore SF, Yang G, Carroll MP, Wei AH, Perl AE.: Acquired BCL2 variants associated with venetoclax resistance in acute myeloid leukemia Blood Adv : 2024.

Chow RD, Velu P, Deihimi S, Belman J, Youn A, Shah N, Luger SM, Carroll MP, Morrissette J, Bowman RL.: Early drivers of clonal hematopoiesis shape the evolutionary trajectories of de novo acute myeloid leukemia medRxiv : 2024.

Bandyopadhyay S, Duffy MP, Ahn KJ, Sussman JH, Pang M, Smith D, Duncan G, Zhang I, Huang J, Lin Y, Xiong B, Imtiaz T, Chen CH, Thadi A, Chen C, Xu J, Reichart M, Martinez Z, Diorio C, Chen C, Pillai V, Snaith O, Oldridge D, Bhattacharyya S, Maillard I, Carroll M, Nelson C, Qin L, Tan K.: Mapping the cellular biogeography of human bone marrow niches using single-cell transcriptomics and proteomic imaging Cell 187 : 3120-3140,2024.

Liu X, Devadiga SA, Stanley RF, Morrow RM, Janssen KA, Quesnel-Vallières M, Pomp O, Moverley AA, Li C, Skuli N, Carroll M, Huang J, Wallace DC, Lynch KW, Abdel-Wahab O, Klein PS.: A mitochondrial surveillance mechanism activated by SRSF2 mutations in hematologic malignancies J Clin Invest 134 : e175619,2024.

Hasanali ZS, Garfall AL, Burzenski L, Shultz LD, Tang Y, Kadu S, Sheppard NC, Liu W, Dopkin D, Vogl DT, Cohen AD, Waxman AJ, Susanibar-Adaniya SP, Carroll M, Stadtmauer EA, Allman D.: Human IL-6 fosters long-term engraftment of patient-derived disease-driving myeloma cells in immunodeficient mice JCI Insight 9 : e177300,2024.

Sung PJ, Selvam M, Riedel SS, Xie HM, Bryant K, Manning B, Wertheim GB, Kulej K, Pham L, Bowman RL, Peresie J, Nemeth MJ, Levine RL, Garcia BA, Meyer SE, Sidoli S, Bernt KM, Carroll M.: FLT3 tyrosine kinase inhibition modulates PRC2 and promotes differentiation in acute myeloid leukemia Leukemia : 2024.

Quesnel-Vallières M, Schultz DC, Orlenko A, Lo Y, Moore J, Ritchie M, Roth D, Carroll M, Barash Y, Lynch KW, Cherry S.: Trametinib Sensitivity is Defined by a Myeloid Differentiation Profile in Acute Myeloid Leukemia Drugs R D : 2024.

Chen DW, Fan JM, Schrey JM, Mitchell DV, Jung SK, Hurwitz SN, Perez EB, Muraro MJ, Carroll M, Taylor DM, Kurre P.: Inflammatory recruitment of healthy hematopoietic stem and progenitor cells in the acute myeloid leukemia niche Leukemia : 2024.

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Academic Contact Information

Room 715, BRB II/III
421 Curie Blvd.
Philadelphia, PA 19104
Phone: 215-573-5217