title: Pre-B cell receptor-mediated cell cycle arrest in Philadelphia chromosome-positive acute lymphoblastic leukemia requires IKAROS function.
abstract: B cell lineage acute lymphoblastic leukemia (ALL) arises in virtually all cases from B cell precursors that are arrested at pre-B cell receptor-dependent stages. The Philadelphia chromosome-positive (Ph(+)) subtype of ALL accounts for 25-30% of cases of adult ALL, has the most unfavorable clinical outcome among all ALL subtypes and is defined by the oncogenic BCR-ABL1 kinase and deletions of the IKAROS gene in >80% of cases. Here, we demonstrate that the pre-B cell receptor functions as a tumor suppressor upstream of IKAROS through induction of cell cycle arrest in Ph(+) ALL cells. Pre-B cell receptor-mediated cell cycle arrest in Ph(+) ALL cells critically depends on IKAROS function, and is reversed by coexpression of the dominant-negative IKAROS splice variant IK6. IKAROS also promotes tumor suppression through cooperation with downstream molecules of the pre-B cell receptor signaling pathway, even if expression of the pre-B cell receptor itself is compromised. In this case, IKAROS redirects oncogenic BCR-ABL1 tyrosine kinase signaling from SRC kinase-activation to SLP65, which functions as a critical tumor suppressor downstream of the pre-B cell receptor. These findings provide a rationale for the surprisingly high frequency of IKAROS deletions in Ph(+) ALL and identify IKAROS-mediated cell cycle exit as the endpoint of an emerging pathway of pre-B cell receptor-mediated tumor suppression.
authors.affiliation: Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90027, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Trageser
authors.forename: Ilaria
authors.initials: I
authors.lastname: Iacobucci
authors.forename: Rahul
authors.initials: R
authors.lastname: Nahar
authors.forename: Cihangir
authors.initials: C
authors.lastname: Duy
authors.forename: Gregor
authors.initials: G
authors.lastname: von Levetzow
authors.forename: Lars
authors.initials: L
authors.lastname: Klemm
authors.forename: Eugene
authors.initials: E
authors.lastname: Park
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schuh
authors.forename: Tanja
authors.initials: T
authors.lastname: Gruber
authors.forename: Sebastian
authors.initials: S
authors.lastname: Herzog
authors.forename: Yong-mi
authors.initials: YM
authors.lastname: Kim
authors.forename: Wolf-Karsten
authors.initials: WK
authors.lastname: Hofmann
authors.forename: Aihong
authors.initials: A
authors.lastname: Li
authors.forename: Clelia Tiziana
authors.initials: CT
authors.lastname: Storlazzi
authors.forename: Hans-Martin
authors.initials: HM
authors.lastname: Jäck
authors.forename: John
authors.initials: J
authors.lastname: Groffen
authors.forename: Giovanni
authors.initials: G
authors.lastname: Martinelli
authors.forename: Nora
authors.initials: N
authors.lastname: Heisterkamp
authors.forename: Hassan
authors.initials: H
authors.lastname: Jumaa
authors.forename: Markus
authors.initials: M
authors.lastname: Müschen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D000328:Adult; D000818:Animals; D002453:Cell Cycle; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000276:immunology; D015536:Down-Regulation; D017353:Gene Deletion; D016313:Genes, abl; D006801:Humans; D051740:Ikaros Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D054403:Leukemia, Prolymphocytic, B-Cell / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010677:Philadelphia Chromosome; D054420:Pre-B Cell Receptors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C113939:B cell linker protein; C497239:IKZF1 protein, human; D054420:Pre-B Cell Receptors; D051740:Ikaros Transcription Factor