title: STAT5 is crucial to maintain leukemic stem cells in acute myelogenous leukemias induced by MOZ-TIF2.
abstract: MOZ-TIF2 is a leukemogenic fusion oncoprotein that confers self-renewal capability to hematopoietic progenitor cells and induces acute myelogenous leukemia (AML) with long latency in bone marrow transplantation assays. Here, we report that FLT3-ITD transforms hematopoietic cells in cooperation with MOZ-TIF2 in vitro and in vivo. Coexpression of FLT3-ITD confers growth factor independent survival/proliferation, shortens disease latency, and results in an increase in the number of leukemic stem cells (LSC). We show that STAT5, a major effector of aberrant FLT3-ITD signal transduction, is both necessary and sufficient for this cooperative effect. In addition, STAT5 signaling is essential for MOZ-TIF2-induced leukemic transformation itself. Lack of STAT5 in fetal liver cells caused rapid differentiation and loss of replating capacity of MOZ-TIF2-transduced cells enriched for LSCs. Furthermore, mice serially transplanted with Stat5(-/-) MOZ-TIF2 leukemic cells develop AML with longer disease latency and finally incomplete penetrance when compared with mice transplanted with Stat5(+/+) MOZ-TIF2 leukemic cells. These data suggest that STAT5AB is required for the self-renewal of LSCs and represents a combined signaling node of FLT3-ITD and MOZ-TIF2 driven leukemogenesis. Therefore, targeting aberrantly activated STAT5 or rewired downstream signaling pathways may be a promising therapeutic option.
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Winnie F
authors.initials: WF
authors.lastname: Tam
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Hähnel
authors.forename: Andrea
authors.initials: A
authors.lastname: Schüler
authors.forename: Benjamin H
authors.initials: BH
authors.lastname: Lee
authors.forename: Rachel
authors.initials: R
authors.lastname: Okabe
authors.forename: Nan
authors.initials: N
authors.lastname: Zhu
authors.forename: Saskia V
authors.initials: SV
authors.lastname: Pante
authors.forename: Glen
authors.initials: G
authors.lastname: Raffel
authors.forename: Thomas
authors.initials: T
authors.lastname: Mercher
authors.forename: Gerlinde
authors.initials: G
authors.lastname: Wernig
authors.forename: Ernesto
authors.initials: E
authors.lastname: Bockamp
authors.forename: Daniel
authors.initials: D
authors.lastname: Sasca
authors.forename: Andreas
authors.initials: A
authors.lastname: Kreft
authors.forename: Gertraud W
authors.initials: GW
authors.lastname: Robinson
authors.forename: Lothar
authors.initials: L
authors.lastname: Hennighausen
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
authors.forename: Thomas
authors.initials: T
authors.lastname: Kindler
mesh_terms: D000818:Animals; D015139:Blotting, Southern; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D005434:Flow Cytometry; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D015514:Oncogene Proteins, Fusion; D050799:STAT5 Transcription Factor