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

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.

Palmisiano N, Jeschke G, Wilde L, Alpdogan O, Carabasi M, Filicko-O'Hara J, Grosso D, Klumpp T, Martinez U, Wagner J, Carroll MP, Perl A, Kasner M.: A Phase I Trial of Sirolimus with "7&3" Induction Chemotherapy in Patients with Newly Diagnosed Acute Myeloid Leukemia Cancers (Basel) 15 : 5129,2023.

Lee I, Doepner M, Weissenrieder J, Majer AD, Mercado S, Estell A, Natale CA, Sung PJ, Foskett JK, Carroll MP, Ridky TW.: LNS8801 inhibits Acute Myeloid Leukemia by Inducing the Production of Reactive Oxygen Species and Activating the Endoplasmic Reticulum Stress Pathway Cancer Res Commun 3 : 1594-1606,2023.

Sabatier M, Birsen R, Lauture L, Mouche S, Angelino P, Dehairs J, Goupille L, Boussaid I, Heiblig M, Boet E, Sahal A, Saland E, Santos JC, Armengol M, Fernandez-Serrano M, Farge T, Cognet G, Simonetta F, Pignon C, Graffeuil A, Mazzotti C, Avet-Loiseau H, Delos O, Bertrand-Michel J, Chedru A, Dembitz V, Gallipoli P, Anstee NS, Loo S, Wei AH, Carroll M, Goubard A, Castellano R, Collette Y, Vergez F, Mansat-De Mas V, Bertoli S, Tavitian S, Picard M, Recher C, Bourges-Abella N, Granat F, Kosmider O, Sujobert P, Colsch B, Joffre C, Stuani L, Swinnen JV, Guillou H, Roue G, Hakim N, Dejean AS, Tsantoulis P, Larrue C, Bouscary D, Tamburini J, Sarry JE.: C/EBPa confers dependence to fatty acid anabolic pathways and vulnerability to lipid oxidative stress-induced ferroptosis in FLT3-mutant leukemia Cancer Discov : 2023.

Kumar A, Taghi Khani A, Duault C, Aramburo S, Sanchez Ortiz A, Lee SJ, Chan A, McDonald T, Huang M, Lacayo NJ, Sakamoto KM, Yu J, Hurtz C, Carroll M, Tasian SK, Ghoda L, Marcucci G, Gu Z, Rosen ST, Armenian S, Izraeli S, Chen CW, Caligiuri MA, Forman SJ, Maecker HT, Swaminathan S.: Intrinsic suppression of type I interferon production underlies the therapeutic efficacy of IL-15-producing natural killer cells in B-cell acute lymphoblastic leukemia J Immunother Cancer : 2023.

Matthews AH, Perl AE, Luger SM, Gill SI, Lai C, Porter DL, Skuli S, Bruno XJ, Carroll MP, Freyer CW, Carulli A, Babushok DV, Frey NV, Hexner EO, Martin ME, McCurdy SR, Stadtmauer EA, Loren AW, Paralkar VR, Maillard IP, Pratz KW.: Real-world effectiveness of intensive chemotherapy with 7&3 versus venetoclax and hypomethylating agent in acute myeloid leukemia Am J Hematol : 2023.

Matthews AH, Pratz KW, Carroll MP.: Targeting Menin and CD47 to Address Unmet Needs in Acute Myeloid Leukemia Cancers (Basel) 14 : 5906,2022.

Liu Y, Li Q, Alikarami F, Barrett DR, Mahdavi L, Li H, Tang S, Khan TA, Michino M, Hill C, Song L, Yang L, Li Y, Pokharel SP, Stamford AW, Liverton N, Renzetti LM, Taylor S, Watt GF, Ladduwahetty T, Kargman S, Meinke PT, Foley MA, Shi J, Li H, Carroll M, Chen CW, Gardini A, Maillard I, Huggins DJ, Bernt KM, Wan L.: Small-Molecule Inhibition of the Acyl-Lysine Reader ENL as a Strategy against Acute Myeloid Leukemia Cancer Discov 12 : 2684-2709,2022.

Rapaport F, Seier K, Neelamraju Y, Hassane D, Baslan T, Gildea DT, Haddox S, Lee T, Murdock HM, Sheridan C, Thurmond A, Wang L, Carroll M, Cripe LD, Fernandez H, Mason CE, Paietta E, Roboz GJ, Sun Z, Tallman MS, Zhang Y, Gönen M, Levine R, Melnick AM, Kleppe M, Garrett-Bakelman FE.: Integrative analysis identifies an older female-linked AML patient group with better risk in ECOG-ACRIN Cancer Research Group's clinical trial E3999 Blood Cancer J 12 : 137,2022.

Vergez F, Largeaud L, Bertoli S, Nicolau ML, Rieu JB, Vergnolle I, Saland E, Sarry A, Tavitian S, Huguet F, Picard M, Vial JP, Lechevalier N, Bidet A, Dumas PY, Pigneux A, Luquet I, Mansat-De Mas V, Delabesse E, Carroll M, Danet-Desnoyers G, Sarry JE, Récher C.: Phenotypically-defined stages of leukemia arrest predict main driver mutations subgroups, and outcome in acute myeloid leukemia Blood Cancer J 12 : 117,2022.

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Academic Contact Information

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