Cooperating mutations in AML: Functional dissection of the cooperating network of recurrent mutations of RUNX1, ASXL1 and IDH2
Final Report Abstract
After generation of BMT and primary Runx1/Asxl1/Idh1 mouse models we concluded that the probability of success and moreover the novelty of these project was low since the phenotype of the mice did not result in an AML and was similar to Runx1 deleted mice alone. I therefore changed my work topic on a number of independent projects. Amongst others, I investigated the role of PRMT5 in MPN pathogenesis and aimed to elucidate key PRMT5 targets contributing to MPN maintenance. PRMT5 is overexpressed in primary MPN cells and PRMT5 inhibition potently reduced MPN cell proliferation ex vivo. PRMT5 inhibition was efficacious at reversing elevated hematocrit, leukocytosis and splenomegaly in a model of JAK2V617F+ polycythemia vera (PV) and leukocyte and platelet counts, hepatosplenomegaly and fibrosis in the MPLW515L model of myelofibrosis (MF). Dual targeting of JAK and PRMT5 was superior to JAK/PRMT5 inhibitor, further decreasing elevated counts and extramedullary hematopoiesis in vivo. PRMT5 inhibition reduced expression of E2F targets and altered the methylation status of E2F1 leading to attenuated DNA damage repair, cell cycle arrest and increased apoptosis. Our data link PRMT5 to E2F1 regulatory function and MPN cell survival and provide a strong mechanistic rationale for clinical trials of PRMT5 inhibitors in MPN. Pharmacological inhibition of PRMT5 alters the methylation status of E2F1 and shows efficacy in JAK2V617F/MPLW515L MPN models and primary samples. PRMT5 represents a potential novel therapeutic target for MPN, which is now being clinically evaluated. Results from this project have been used to support the planning and scientifical rational for the clinical investigation of a novel PRMT5 inhibitor in MPN in a Phase I clinical trial (NCT03886831).
Publications
- Next-Generation Sequencing and Detection of Minimal Residual Disease in Acute Myeloid Leukemia: Ready for Clinical Practice? JAMA. 2015 Aug 25;314(8):778-80
Pastore F, Levine RL
(See online at https://doi.org/10.1001/jama.2015.9452) - DNMT3A mutations promote anthracycline resistance in acute myeloid leukemia via impaired nucleosome remodeling. Nat Med. 2016 Dec;22(12):1488-1495
Guryanova OA, Shank K, Spitzer B, Luciani L, Koche RP, Garrett-Bakelman FE, Ganzel C, Durham BH, Mohanty A, Hoermann G, Rivera SA, Chramiec AG, Pronier E, Bastian L, Keller MD, Tovbin D, Loizou E, Weinstein AR, Gonzalez AR, Lieu YK, Rowe JM, Pastore F, McKenney AS, Krivtsov AV, Sperr WR, Cross JR, Mason CE, Tallman MS, Arcila ME, Abdel-Wahab O, Armstrong SA, Kubicek S, Staber PB, Gönen M, Paietta EM, Melnick AM, Nimer SD, Mukherjee S, Levine RL
(See online at https://doi.org/10.1038/nm.4210) - Epigenetic regulators and their impact on therapy in acute myeloid leukemia. Haematologica. 2016 Mar;101(3):269-78
Pastore F, Levine RL.
(See online at https://doi.org/10.3324/haematol.2015.140822) - Evolution of Cytogenetically Normal Acute Myeloid Leukemia During Therapy and Relapse: An Exome Sequencing Study of 50 Patients. Clin Cancer Res. 2018 Apr 1;24(7):1716-1726
Greif PA, Hartmann L, Vosberg S, Stief SM, Mattes R, Hellmann I, Metzeler KH, Herold T, Bamopoulos SA, Kerbs P, Jurinovic V, Schumacher D, Pastore F, Bräundl K, Zellmeier E, Ksienzyk B, Konstandin NP, Schneider S, Graf A, Krebs S, Blum H, Neumann M, Baldus CD, Bohlander SK, Wolf S, Görlich D, Berdel WE, Wörmann BJ, Hiddemann W, Spiekermann K
(See online at https://doi.org/10.1158/1078-0432.CCR-17-2344) - Genetic heterogeneity of cytogenetically normal AML with mutations of CEBPA. Blood Adv. 2018 Oct 23;2(20):2724-2731
Konstandin NP, Pastore F, Herold T, Dufour A, Rothenberg-Thurley M, Hinrichsen T, Ksienzyk B, Tschuri S, Schneider S, Hoster E, Berdel WE, Woermann BJ, Sauerland MC, Braess J, Bohlander SK, Klein HG, Hiddemann W, Metzeler KH, Spiekermann K
(See online at https://doi.org/10.1182/bloodadvances.2018016840) - PHF6 and DNMT3A Mutations are Enriched in Distinct Subgroups of Mixed Phenotype Acute Leukemia with T-lineage Differentiation. Blood Adv. 2018 Dec 11;2(23):3526-3539
Xiao W, Bharadwaj M, Pastore F, Getta B, Hultquist A, Famulare C, Max L, Medina JS, Farnhoud N, Patel MA, Gao Q, Lewis N, Pichardo J, Baik J, Shaffer B, Giralt S, Rampal RK, Delvin S, Cimera R, Zhang Y, Arcila ME, Papaemmanuil E, Levine RL, and Roshal M
(See online at https://doi.org/10.1182/bloodadvances.2018023531) - Targeting the CALR Interactome in Myeloproliferative Neoplasms. JCI Insight. 2018 Nov 15; 3(22): e122703
Pronier E, Cifani P, Merlinsky T, Berman KB, Hanasoge Somasundara AV, Rampal RK, LaCava J, Wei KE, Pastore F, Maag JLV, Park J, Koche R, Kentsis A, Levine RL
(See online at https://doi.org/10.1172/jci.insight.122703)
