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. 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.