Article

Pre-B cell receptor-mediated cell cycle arrest in Philadelphia chromosome-positive acute lymphoblastic leukemia requires IKAROS function. J Exp Med

Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90027, USA.
Journal of Experimental Medicine (Impact Factor: 13.91). 09/2009; 206(8):1739-53. DOI: 10.1084/jem.20090004
Source: PubMed

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.

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Available from: Yong-Mi Kim, Aug 26, 2015
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    • ". Similar to this potentiated response to T-cell receptor signaling, in Ikaros-mutated pre-B-cell ALL, there appears to be increased sensitivity to proliferation signals mediated by the pre-B-cell receptor [Merkenschlager, 2010; Trageser et al. 2009; Nera et al. 2006]. During normal B-cell development , as pro-B cells rearrange their heavy chain, ligand-autonomous signaling via the pre-B cell receptor (pre-BCR) causes cells to cycle, expand and transition into the large pre-B-cell stage of development. "
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    • "Consistent with a role in the termination of pre-BCR signaling, patients lacking SLP65 show a block in Bcell development [48] and SLP65 deficiency is associated with enhanced pre-B cell proliferation and pre-B-cell leukaemia in mouse [4] and in human [49]. In addition, Ikaros appears to promote SLP- 65 activation by as yet unknown mechanisms, and is required for cell cycle arrest in response to pre-BCR signaling [46]. SLP65 also has a role in promoting Ig kappa rearrangement through a pathway that involves Foxo transcription factors [50], the interferon regulatory factors 4 and 8, which are implicated in regulating Aiolos expression [47], and perhaps Ikaros itself [16]. "
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