Modulation of the myeloid differentiation block in acute myeloid leukemia II
Final Report Abstract
The main proposal was extended by an additional application for funding of a Syrian refugee as a scientist for integration into the German science system. In a certain type of AML, characterized by MLL fusions, we found that the oncogene MN1 plays an essential role for the ability of these cells to induce leukemia. We also developed a novel therapeutic approach using anti-MN1 siRNA, a small nucleotide sequence that blocks the production of MN1 protein. We developed a lipid nanoparticle-mediated siRNA delivery technology to target leukemogenic fusion genes in primary AML cells to be used as differentiation-inducing therapeutic agents. We proved its efficacy in human AML in vivo and aim to further develop this technology for clinical use. Using xenograft models, we have identified effective drug combinations that inform future clinical trials. In summary, the funding enabled us to further dissect the mechanisms how myeloid differentiation is blocked in AML cells.
Publications
- RNA interference efficiently targets human leukemia driven by a fusion oncogene in vivo. Leukemia. 2018 Jan; 32(1): 224–226
Jyotsana N, Sharma A, Chaturvedi A, Scherr M, Kuchenbauer F, Sajti L, Barchanski A, Lindner R, Noyan F, Sühs KW, Grote- Koska D, Brand K, Vornlocher HP, Stanulla M, Bornhauser B, Bourquin JP, Eder M, Thol F, Ganser A, Humphries RK, Ramsay E, Cullis P, Heuser M
(See online at https://doi.org/10.1038/leu.2017.269) - Lipid nanoparticle-mediated siRNA delivery for safe targeting of human CML in vivo. Ann Hematol. 2019; 98(8):1905-1918
Jyotsana N, Sharma A, Chaturvedi A, Budida R, Scherr M, Kuchenbauer F, Lindner R, Noyan F, Sühs KW, Stangel M, Grote-Koska D, Brand K, Vornlocher HP, Eder M, Thol F, Ganser A, Humphries RK, Ramsay E, Cullis P, Heuser M
(See online at https://doi.org/10.1007/s00277-019-03713-y) - Combination treatment of an IDH1 inhibitor with chemotherapy in IDH1 mutant acute myeloid leukemia. Ann Hematol. 2020
Gupta C, Kaulfuss S, Görlich K, Othman B, Chaturvedi A, Heuser M
(See online at https://doi.org/10.1007/s00277-020-04001-w) - In vivo efficacy of mutant IDH1 inhibitor HMS-101 and structural resolution of distinct binding site. Leukemia. 2020; 34(2):416-426
Chaturvedi A, Goparaju R, Gupta C, Weder J, Klünemann T, Araujo Cruz MM, Kloos A, Goerlich K, Schottmann R, Othman B, Struys EA, Bähre H, Grote-Koska D, Brand K, Ganser A, Preller M, Heuser M
(See online at https://doi.org/10.1038/s41375-019-0582-x) - Meningioma 1 is indispensable for mixed lineage leukemia-rearranged acute myeloid leukemia. Haematologica. 2020 May;105(5):1294-1305
Sharma A, Jyotsana N, Gabdoulline R, Heckl D, Kuchenbauer F, Slany RK, Ganser A, Heuser M
(See online at https://doi.org/10.3324/haematol.2018.211201)
