title: MLL-AF9- and HOXA9-mediated acute myeloid leukemia stem cell self-renewal requires JMJD1C.
abstract: Self-renewal is a hallmark of both hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs); therefore, the identification of mechanisms that are required for LSC, but not HSC, function could provide therapeutic opportunities that are more effective and less toxic than current treatments. Here, we employed an in vivo shRNA screen and identified jumonji domain-containing protein JMJD1C as an important driver of MLL-AF9 leukemia. Using a conditional mouse model, we showed that loss of JMJD1C substantially decreased LSC frequency and caused differentiation of MLL-AF9- and homeobox A9-driven (HOXA9-driven) leukemias. We determined that JMJD1C directly interacts with HOXA9 and modulates a HOXA9-controlled gene-expression program. In contrast, loss of JMJD1C led to only minor defects in blood homeostasis and modest effects on HSC self-renewal. Together, these data establish JMJD1C as an important mediator of MLL-AF9- and HOXA9-driven LSC function that is largely dispensable for HSC function.
authors.forename: Nan
authors.initials: N
authors.lastname: Zhu
authors.forename: Mo
authors.initials: M
authors.lastname: Chen
authors.forename: Rowena
authors.initials: R
authors.lastname: Eng
authors.forename: Joshua
authors.initials: J
authors.lastname: DeJong
authors.forename: Amit U
authors.initials: AU
authors.lastname: Sinha
authors.forename: Noushin F
authors.initials: NF
authors.lastname: Rahnamay
authors.forename: Richard
authors.initials: R
authors.lastname: Koche
authors.forename: Fatima
authors.initials: F
authors.lastname: Al-Shahrour
authors.forename: Janna C
authors.initials: JC
authors.lastname: Minehart
authors.forename: Chun-Wei
authors.initials: CW
authors.lastname: Chen
authors.forename: Aniruddha J
authors.initials: AJ
authors.lastname: Deshpande
authors.forename: Haiming
authors.initials: H
authors.lastname: Xu
authors.forename: S Haihua
authors.initials: SH
authors.lastname: Chu
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Ebert
authors.forename: Robert G
authors.initials: RG
authors.lastname: Roeder
authors.forename: Scott A
authors.initials: SA
authors.lastname: Armstrong
mesh_terms: D000818:Animals; D000066673:Cell Self Renewal; D015870:Gene Expression; D006412:Hematopoietic Stem Cells / Q000502:physiology; D018398:Homeodomain Proteins / Q000502:physiology*; D056484:Jumonji Domain-Containing Histone Demethylases / Q000502:physiology*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000502:physiology*; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D018398:Homeodomain Proteins; C551356:MLL-AF9 fusion protein, mouse; D015514:Oncogene Proteins, Fusion; C097899:homeobox protein HOXA9; C554520:JMJD1c protein, mouse; D056484:Jumonji Domain-Containing Histone Demethylases