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: 12.52). 09/2009; 206(8):1739-53. DOI: 10.1084/jem.20090004
Source: PubMed


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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    • "In addition, Ikaros suppresses pre-B cell proliferation, thus allowing for a correct differentiation program [11]. Loss of Ikaros activity is indeed observed in more than 80% of Ph+ ALL [38]. Ikaros proteins also play an important role in monocyte/macrophage development [4]. "
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    ABSTRACT: The Ikaros gene encodes a Krüppel-like zinc-finger transcription factor involved in hematopoiesis regulation. Ikaros has been established as one of the most clinically relevant tumor suppressors in several hematological malignancies. In fact, expression of dominant negative Ikaros isoforms is associated with adult B-cell acute lymphoblastic leukemia, myelodysplastic syndrome, acute myeloid leukemia and adult and juvenile chronic myeloid leukemia. Here, we report the isolation of a novel, non-canonical Ikaros splice variant, called Ikaros 11 (Ik11). Ik11 is structurally related to known dominant negative Ikaros isoforms, due to the lack of a functional DNA-binding domain. Interestingly, Ik11 is the first Ikaros splice variant missing the transcriptional activation domain. Indeed, we demonstrated that Ik11 works as a dominant negative protein, being able to dimerize with Ikaros DNA-binding isoforms and inhibit their functions, at least in part by retaining them in the cytoplasm. Notably, we demonstrated that Ik11 is the first dominant negative Ikaros isoform to be aberrantly expressed in B-cell lymphoproliferative disorders, such as chronic lymphocytic leukemia. Aberrant expression of Ik11 interferes with both proliferation and apoptotic pathways, providing a mechanism for Ik11 involvement in tumor pathogenesis. Thus, Ik11 could represent a novel marker for B-cell lymphoproliferative disorders.
    PLoS ONE 07/2013; 8(7):e68080. DOI:10.1371/journal.pone.0068080 · 3.23 Impact Factor
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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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    ABSTRACT: We report that t(1;19) ALL cells universally exhibit expression of and dependence on the cell surface receptor ROR1. We further identify t(1;19) ALL cell sensitivity to the kinase inhibitor dasatinib due to its inhibition of the pre-B cell receptor (pre-BCR) signaling complex. These phenotypes are a consequence of developmental arrest at an intermediate/late stage of B-lineage maturation. Additionally, inhibition of pre-BCR signaling induces further ROR1 upregulation, and we identify distinct ROR1 and pre-BCR downstream signaling pathways that are modulated in a counterbalancing manner-both leading to AKT phosphorylation. Consistent with this, AKT phosphorylation is transiently eliminated after dasatinib treatment, but is partially restored following dasatinib potentiation of ROR1 expression. Consequently, ROR1 silencing accentuates dasatinib killing of t(1;19) ALL cells.
    Cancer cell 11/2012; 22(5):656-67. DOI:10.1016/j.ccr.2012.08.027 · 23.52 Impact Factor
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    • "Downstream of the hematopoietic stem cells, Ikaros restricts the multilineage potential of lymphoid and myeloid progenitors by repressing lineage-inappropriate genetic programs including hematopoietic stem cell–specific genes. Deletions result in the majority of cases in the production of isoforms unable to bind the DNA, which determine a block of differentiation, increased proliferation [35], continuous self-renewal and accumulation of DNA damage. "
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    ABSTRACT: Deletions of IKAROS (IKZF1) frequently occur in B-cell precursor acute lymphoblastic leukemia (B-ALL) but the mechanisms by which they influence pathogenesis are unclear. To address this issue, a cohort of 144 adult B-ALL patients (106 BCR-ABL1-positive and 38 B-ALL negative for known molecular rearrangements) was screened for IKZF1 deletions by single nucleotide polymorphism (SNP) arrays; a sub-cohort of these patients (44%) was then analyzed for gene expression profiling. Total or partial deletions of IKZF1 were more frequent in BCR-ABL1-positive than in BCR-ABL1-negative B-ALL cases (75% vs 58%, respectively, p = 0.04). Comparison of the gene expression signatures of patients carrying IKZF1 deletion vs those without showed a unique signature featured by down-regulation of B-cell lineage and DNA repair genes and up-regulation of genes involved in cell cycle, JAK-STAT signalling and stem cell self-renewal. Through chromatin immunoprecipitation and luciferase reporter assays we corroborated these findings both in vivo and in vitro, showing that Ikaros deleted isoforms lacked the ability to directly regulate a large group of the genes in the signature, such as IGLL1, BLK, EBF1, MSH2, BUB3, ETV6, YES1, CDKN1A (p21), CDKN2C (p18) and MCL1. Here we identified and validated for the first time molecular pathways specifically controlled by IKZF1, shedding light into IKZF1 role in B-ALL pathogenesis.
    PLoS ONE 07/2012; 7(7):e40934. DOI:10.1371/journal.pone.0040934 · 3.23 Impact Factor
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