title: Mutant IDH1 promotes leukemogenesis in vivo and can be specifically targeted in human AML.
abstract: Mutations in the metabolic enzymes isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) are frequently found in glioma, acute myeloid leukemia (AML), melanoma, thyroid cancer, and chondrosarcoma patients. Mutant IDH produces 2-hydroxyglutarate (2HG), which induces histone- and DNA-hypermethylation through inhibition of epigenetic regulators. We investigated the role of mutant IDH1 using the mouse transplantation assay. Mutant IDH1 alone did not transform hematopoietic cells during 5 months of observation. However, mutant IDH1 greatly accelerated onset of myeloproliferative disease-like myeloid leukemia in mice in cooperation with HoxA9 with a mean latency of 83 days compared with cells expressing HoxA9 and wild-type IDH1 or a control vector (167 and 210 days, respectively, P = .001). Mutant IDH1 accelerated cell-cycle transition through repression of cyclin-dependent kinase inhibitors Cdkn2a and Cdkn2b, and activated mitogen-activated protein kinase signaling. By computational screening, we identified an inhibitor of mutant IDH1, which inhibited mutant IDH1 cells and lowered 2HG levels in vitro, and efficiently blocked colony formation of AML cells from IDH1-mutated patients but not of normal CD34(+) bone marrow cells. These data demonstrate that mutant IDH1 has oncogenic activity in vivo and suggest that it is a promising therapeutic target in human AML cells.
authors: Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation.
authors: Anuhar
authors: A
authors: Chaturvedi
authors: Michelle Maria
authors: MM
authors: Araujo Cruz
authors: Nidhi
authors: N
authors: Jyotsana
authors: Amit
authors: A
authors: Sharma
authors: Haiyang
authors: H
authors: Yun
authors: Kerstin
authors: K
authors: Görlich
authors: Martin
authors: M
authors: Wichmann
authors: Adrian
authors: A
authors: Schwarzer
authors: Matthias
authors: M
authors: Preller
authors: Felicitas
authors: F
authors: Thol
authors: Johann
authors: J
authors: Meyer
authors: Reinhard
authors: R
authors: Haemmerle
authors: Eduard A
authors: EA
authors: Struys
authors: Erwin E
authors: EE
authors: Jansen
authors: Ute
authors: U
authors: Modlich
authors: Zhixiong
authors: Z
authors: Li
authors: Laura M
authors: LM
authors: Sly
authors: Robert
authors: R
authors: Geffers
authors: Robert
authors: R
authors: Lindner
authors: Dietmar J
authors: DJ
authors: Manstein
authors: Ulrich
authors: U
authors: Lehmann
authors: Jürgen
authors: J
authors: Krauter
authors: Arnold
authors: A
authors: Ganser
authors: Michael
authors: M
authors: Heuser
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis; D016026:Bone Marrow Transplantation; D002453:Cell Cycle; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009154:Mutation; D055815:Young Adult
chemical_list: D018952:Antigens, CD34; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human