Pre-B cell receptor-mediated cell cycle arrest in Philadelphia chromosome-positive acute lymphoblastic leukemia requires IKAROS function.
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.
Trageser
Daniel
D
Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90027, USA.
Iacobucci
Ilaria
I
Nahar
Rahul
R
Duy
Cihangir
C
von Levetzow
Gregor
G
Klemm
Lars
L
Park
Eugene
E
Schuh
Wolfgang
W
Gruber
Tanja
T
Herzog
Sebastian
S
Kim
Yong-mi
YM
Hofmann
Wolf-Karsten
WK
Li
Aihong
A
Storlazzi
Clelia Tiziana
CT
Jäck
Hans-Martin
HM
Groffen
John
J
Martinelli
Giovanni
G
Heisterkamp
Nora
N
Jumaa
Hassan
H
Müschen
Markus
M
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
D048868:Adaptor Proteins, Signal Transducing; C113939:B cell linker protein; C497239:IKZF1 protein, human; D054420:Pre-B Cell Receptors; D051740:Ikaros Transcription Factor