Marina Konopleva, M.D., Ph.D.

My laboratory and clinical research are focusing on novel agents in acute myeloid leukemia. The main area of active investigations is attacking apoptotic machinery of leukemia cells by depriving them from key pro-survival inputs by targeting BCL-2, BCL-XL, Mcl-1 by small molecule inhibitors and degraders. We continue studies characterizing mechanisms of resistance to BCL-2 inhibition and identifying novel combinatorial strategies with immune therapies and signaling inhibitors. My lab is interested in studying the biology and therapeutic targeting of leukemia-initiating cells, with novel multi-targeted bispecific T- or NK-engagers, antibody-drug conjugates and CART cells. We further aim at identifying key targets in maintenance and eradication of minimal residual disease (MRD) in acute myeloid leukemia (AML). We have studied metabolic states in AML and T-ALL and utilized novel metabolic inhibitors to selectively deprive tumor metabolism, such as glutaminase, OxPhos and fatty acid metabolic inhibitors. Finally, we are interested in understanding the biology and targeting of an aggressive hematologic malignancy Blastic Plasmacytoid Dendritic ell neoplasm (BPDCN), through targeting BCL-2, CD123 and novel cell surface targets with small molecules, antibodies and CART cells. Most robust pre-clinical discoveries have translated into clinical trials, such as venetoclax, metabolic inhibitors and immune modulators.

Pan R, Hogdal LJ, Benito JM, Bucci D, Han L, Borthakur G, Cortes J, DeAngelo DJ, Debose L, Mu H, Döhner H, Gaidzik VI, Galinsky I, Golfman LS, Haferlach T, Harutyunyan KG, Hu J, Leverson JD, Marcucci G, Müschen M, Newman R, Park E, Ruvolo PP, Ruvolo V, Ryan J, Schindela S, Zweidler-McKay P, Stone RM, Kantarjian H, Andreeff M, Konopleva M, Letai AG (co-corresponding last author). Selective BCL-2 Inhibition by ABT-199 Causes On Target Cell Death in Acute Myeloid Leukemia. Cancer Discov 4(3):362-75, 3/2014. e-Pub 12/2013. PMCID: PMC3975047.

Zhang Q, Riley-Gillis B, Han L, Jia Y, Lodi A, Zhang H, Ganesan S, Pan R, Konoplev SN, Sweeney SR, Ryan JA, Jitkova Y, Dunner K, Grosskurth SE, Vijay P, Ghosh S, Lu C, Ma W, Kurtz S, Ruvolo VR, Ma H, Weng CC, Ramage CL, Baran N, Shi C, Cai T, Davis RE, Battula VL, Mi Y, Wang J, DiNardo CD, Andreeff M, Tyner JW, Schimmer A, Letai A, Padua RA, Bueso-Ramos CE, Tiziani S, Leverson J, Popovic R, Konopleva M. Activation of RAS/MAPK pathway confers MCL-1 mediated acquired resistance to BCL-2 inhibitor venetoclax in acute myeloid leukemia. Signal Transduct Target Ther 7(1):51, 2/2022. e-Pub 2/2022. PMID: 35185150.

DiNardo CD, Konopleva MY. A venetoclax bench-to-bedside story. Nat Cancer 2(1):3-5, 1/2021. PMID: 35121895.

Baran N, Lodi A, Dhungana Y,  Herbrich S,  Collins M, Sweeney S,  Pandey R, Skwarska A,  Patel S,  Tremblay M,  Kuruvilla VM,  Cavazos A,  Kaplan  M,  Warmoes MO,  Veiga DT,  Furudate K,  Rojas-Sutterin S, Haman A,  Gareau Y,  Marinier A, Ma H,  Harutyunyan K,  Daher M,  Garcia LM,  Al-Atrash G,  Piya S, Ruvolo V, Yang W,  Shanmugavelandy SS,  Feng N,  Gay J,  Du D,  Yang JJ,  Hoff FW,  Kaminski M,  Tomczak K, Davis  RE, Herranz D,  Ferrando A,  Jabbour EJ, Di Francesco ME,  Teachey DT,  Horton TM,  Kornblau S, Rezvani K, Sauvageau G,  Gagea M, Andreeff M, Takahashi K,  Marszalek JR,  Lorenzi PL, Yu J, Tiziani S, Hoang T, Konopleva M. Inhibition of mitochondrial complex I reverses NOTCH1-driven metabolic reprogramming in T-cell acute lymphoblastic leukemia. Nat Commun. 13(1):2801, 5/2022. PMID:35589701.

Cai T, Gouble A, Black KL, Skwarska A, Naqvi AS, Taylor D, Zhao M, Yuan Q, Sugita M, Zhang Q, Galetto R, Filipe S, Cavazos A, Han L, Kuruvilla V, Ma H, Weng C, Liu CG, Liu X, Konoplev S, Gu J, Tang G, Su X, Al-Atrash G, Ciurea S, Neelapu SS, Lane AA, Kantarjian H, Guzman ML, Pemmaraju N, Smith J, Thomas-Tikhonenko A, Konopleva M. Targeting CD123 in blastic plasmacytoid dendritic cell neoplasm using allogeneic anti-CD123 CAR T cells. Nat Commun 13(1):2228, 4/2022. PMCID: PMC9051102.

Pemmaraju N, Lane AA, Sweet KL, Stein AS, Vasu S, Blum W, Rizzieri DA, Wang ES, Duvic M, Sloan JM, Spence S, Shemesh S, Brooks CL, Balser J, Bergstein I, Lancet JE, Kantarjian HM, Konopleva M. Tagraxofusp in Blastic Plasmacytoid Dendritic-Cell Neoplasm. N Engl J Med 380(17):1628-1637, 4/2019. PMID: 31018069.

Herbrich S, Baran N, Cai T, Weng C, Aitken MJL, Post SM, Henderson J, Shi C, Richard-Carpentier G, Sauvageau G, Baggerly K, Al-Atrash G, Davis RE, Daver N, Zha D, Konopleva M. Overexpression of CD200 is a Stem Cell-Specific Mechanism of Immune Evasion in AML. J Immunother Cancer 9(7):e002968, 7/2021. PMID: 34326171.

Yap TA, Daver N, Mahendra M, Zhang J, Kamiya-Matsuoka C, Meric-Bernstam F, Kantarjian HM, Ravandi F, Collins ME, Francesco MED, Dumbrava EE, Fu S, Gao S, Gay JP, Gera S, Han J, Hong DS, Jabbour EJ, Ju Z, Karp DD, Lodi A, Molina JR, Baran N, Naing A, Ohanian M, Pant S, Pemmaraju N, Bose P, Piha-Paul SA, Rodon J, Salguero C, Sasaki K, Singh AK, Subbiah V, Tsimberidou AM, Xu QA, Yilmaz M, Zhang Q, Li Y, Bristow CA, Bhattacharjee MB, Tiziani S, Heffernan TP, Vellano CP, Jones P, Heijnen CJ, Kavelaars A, Marszalek JR, Konopleva M. (2023). Complex I Inhibitor of Oxidative Phosphorylation in Advanced Solid Tumors and Acute Myeloid Leukemia: Phase I Trials. Nat Med. 29(1), 115-126. PMID: 36658425

Jia Y, Han L, Ramage CL, Wang Z, Weng CC, Yang L, Colla S, Ma H, Zhang W, Andreeff M, Daver N, Jain N, Pemmaraju N, Bhalla K, Mustjoki S, Zhang P, Zheng G, Zhou D, Zhang Q, Konopleva M. (2023). Co-targeting BCL-XL and BCL-2 by PROTAC 753B eliminates leukemia cells and enhances efficacy of chemotherapy by targeting senescent cells. Haematologica 2023 Apr 20 [online ahead of print]. PMID: 37078252