Gene expression changes induced by hypomethylating agent, Azacitidine (AZA) ; IDH1 inhibitor, BAY1436032 (BAY) and combination of BAY and AZA in sorted human (CD45+) cells from bone marrow of IDH1mut Patient derived Xenotransplantation mice model.. Gene expression changes induced by hypomethylating agent, Azacitidine (AZA) ; IDH1 inhibitor, BAY1436032 (BAY) and combination of BAY and AZA in sorted human (CD45+) cells from bone marrow of IDH1mut Patient derived Xenotransplantation mice model.

Mutations in the enzymes IDH1 and IDH2 have been identified in a wide variety of tumors like glioma, chondrosarcoma, thyroid cancer, lymphoma, melanoma, and in acute myeloid leukemia. Mutated IDH1/2 produces the metabolite 2-hydroxyglutarate (2HG), which interferes with epigenetic regulation of gene expression, and thus may promote tumorigenesis. Data for IDH1 inhibitors show that 30-40% of AML patients respond to monotherapy with a median duration of response of 8 months, suggesting that IDH1 inhibitors should be combined with other agents to improve efficacy. BAY 1436032 (BAY) is an oral pan-mutant IDH1 inhibitor currently undergoing phase 1 clinical trials. 5-Azacitidine (AZA) is a hypomethylating agent and can activate key epigenetically silenced pathways in AML cells, leading to an arrest of AML cell proliferation. Overall design: NSG mice were transplanted with cells from human AML patient carrying IDH1mutation. After 60-70% chimerism, mice were treated either with vehicle, azacitidine (1 mg/kg, s.c., days 1 to 5), BAY1436032 (150 mg/kg, p.o., q.d., 4 weeks) or the simultaneous combination of BAY1436032 and azacitidine. Four weeks after treatment, human CD45+ cells were sorted from mouse bone marrow, from which total RNA was extracted and subjected to microarray analysis.