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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    • "A meta-analysis was performed for gene expression microarray analyses of samples from pediatric patients with ALL and normal B cell progenitor populations as previously described (Trageser et al., 2009). Data sets were processed and normalized using the RMA algorithm, and normalization was validated on the basis of even expression levels for a set of seven reference genes (HPRT, COX6B, GUSB, GAPDH, PGK, ACTB, and B2M) among all tissue samples studied. "
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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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