Immunoglobulin heavy chain locus chromosomal translocations in B-cell precursor acute lymphoblastic leukemia: rare clinical curios or potent genetic drivers?

Dyer, Martin J. S.; Akasaka, Takashi; Capasso, Melania; Dusanjh, Palminder; Lee, Yin Fai; Karran, E. Loraine; Nagel, Inga; Vater, Inga; Cario, Gunnar; Siebert, Reiner

doi:10.1182/blood-2009-09-235986

Cited by 58 publications

(54 citation statements)

References 86 publications

(72 reference statements)

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“…A number of groups have demonstrated that CRLF2 alterations occur in 5-7% of all B-ALL and in 60% of B-ALL in children with Down syndrome (21)(22)(23)(24)(25)(26)(27)(28). Most of CRLF2 alterations involve IGH@-CRLF2 rearrangements or PAR1 deletion resulting in overexpression of CRLF2.…”

Section: Thymic Stromal Lymphopoietin (Tslp)mentioning

confidence: 99%

“…Kinase Inhibitor Assays Reveal Potential Therapeutic Targets in TSLP-associated Diseases-Hyperactivation of TSLP/ TSLPR signaling has been reported in a number of diseases such as asthma and leukemias (14,15,(21)(22)(23)(24)(25)(26)(27)(28)93). We propose that some kinase(s) in the TSLP signaling pathway could be potential targets for TSLP-induced diseases and that pharmacological inhibition of these kinases could serve as novel therapeutic strategies for treatment of these diseases.…”

Section: Btk Protein Tyrosine Kinasementioning

confidence: 99%

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TSLP Signaling Network Revealed by SILAC-Based Phosphoproteomics

Zhong

Kim

Chaerkady³

et al. 2012

Molecular & Cellular Proteomics

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Thymic stromal lymphopoietin (TSLP) is a cytokine that plays diverse roles in the regulation of immune responses. TSLP requires a heterodimeric receptor complex consisting of IL-7 receptor ␣ subunit and its unique TSLP receptor (gene symbol CRLF2) to transmit signals in cells. Abnormal TSLP signaling (e.g. overexpression of TSLP or its unique receptor TSLPR) contributes to the development of a number of diseases including asthma and leukemia. However, a detailed understanding of the signaling pathways activated by TSLP remains elusive. In this study, we performed a global quantitative phosphoproteomic analysis of the TSLP signaling network using stable isotope labeling by amino acids in cell culture. By employing titanium dioxide in addition to antiphosphotyrosine antibodies as enrichment methods, we identified 4164 phosphopeptides on 1670 phosphoproteins. Using stable isotope labeling by amino acids in cell culture-based quantitation, we determined that the phosphorylation status of 226 proteins was modulated by TSLP stimulation. Our analysis identified activation of several members of the Src and Tec families of kinases including Btk, Lyn, and Tec by TSLP for the first time. In addition, we report TSLP-induced phosphorylation of protein phosphatases such as Ptpn6 (SHP-1) and Ptpn11 (Shp2), which has also not been reported previously. Co-immunoprecipitation assays showed that Shp2 binds to the adapter protein Gab2 in a TSLP-dependent manner. This is the first demonstration of an inducible protein complex in TSLP signaling. A kinase inhibitor screen revealed that pharmacological inhibition of PI-3 kinase, Jak family kinases, Src family kinases or Btk suppressed TSLP-dependent cellular proliferation making them candidate therapeutic targets in diseases resulting from aberrant TSLP signaling. Our study is the first phosphoproteomic analysis of the TSLP signaling pathway that greatly expands our understanding of TSLP signaling and provides novel therapeutic targets for TSLP/ TSLPR-associated diseases in humans. Molecular & Cellular Proteomics 11: 10.1074/mcp.M112.017764, 1-22, 2012. Thymic stromal lymphopoietin (TSLP)1 is an IL-7-like fourhelix bundle cytokine that was originally identified as a growth factor from the conditioned medium of the Z210R.1 thymic stromal cell line to support B-cell development in the absence of IL-7 (1, 2). TSLP mediates its effects through a heterodimeric receptor complex consisting of IL-7R␣ and a unique TSLP receptor (TSLPR, also known as CRLF2) (3, 4). In humans, epithelial cells are the major source of TSLP (5), which acts on a number of distinctive cell types. TSLP released from airway epithelial cells synergizes with IL-1 and TNF to stimulate the production of high levels of Th2 cytokines by mast cells (6). TSLP can promote the maturation of dendritic cells, thereby driving the Type 2 differentiation of T helper cells (7). Studies have also shown that TSLP enhances proliferation of CD4ϩ and CD8ϩ T cells activated by T-cell receptor stimulation (8, 9). In mice, TSLP can also activ...

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Section: Thymic Stromal Lymphopoietin (Tslp)mentioning

confidence: 99%

Section: Btk Protein Tyrosine Kinasementioning

confidence: 99%

TSLP Signaling Network Revealed by SILAC-Based Phosphoproteomics

Zhong

Kim

Chaerkady³

et al. 2012

Molecular & Cellular Proteomics

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“…For example, a tCGH array used to diagnose and classify B-cell lymphomas, plasma cell neoplasms, and B-ALL might contain all known IGH@ partners, including BCL2, BCL6, CCND1, MALT1, and MYC for mature B-cell lymphomas, FGFR3/MMSET, MAF, MAFB, and CCND3 for multiple myeloma, 73 and CRLF2, ID4, and CEBP family members for B-ALL. 69 Linear amplification primers could readily be designed to identify other recurrent translocations: eg, the t(11;18) BIRC3-MALT1 fusion in MALT lymphoma; t(12;21) ETV6-RUNX1 in B-ALL, ALK rearrangements in anaplastic large T-cell lymphoma; TRA@-TCL1A (alias TCL1) and other TCR gene fusions in T-cell lymphomas and leukemias; and/or MECOM (previously EVI1 and MDS1), NUP214, PDGFRB (previously PDGFR), and FGFR1 fusions in AML and other myeloid stem cell neoplasms. 2 Such arrays would also include probes for recurrent genomic imbalances that are important for tumor classification and prognosis, such as chromosomal deletions at 11q22.3 (ATM), 13q14.3 (MIR15A, MIR16-1), and 17p13.1 (TP53) in chronic lymphocytic leukemia, 74 and deletions involving chromosome 5q and 7q in myeloid stem cell neoplasms.…”

Section: Discussionmentioning

confidence: 99%

“…Although either partner gene can serve as the primary partner, we generally selected the one that had the smaller genomic breakpoint region and therefore required fewer linear amplification primers for complete coverage. Promiscuous 1 fusion partners such as IGH@, MLL, and BCL6 make ideal primary partners, because rearrangements involving scores of alternative secondary partners 63,[67][68][69][70][71] can be detected by amplification using relatively few primers and hybridization to an array representing all known secondary partner loci. IGH@ translocation breakpoints, for example, typically are clustered at paralogous J H , D H , and S H gene segments and can be identified by multiplex amplification with three primers (J H , SpF, S␥F) to detect breakpoints on the der(14) chromosome or, alternatively, with a multiplex set of nine primers (D H 1 to D H 7, SpR, S␥R) to detect breakpoints on the reciprocal derivative chromosome (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Rapid High-Resolution Mapping of Balanced Chromosomal Rearrangements on Tiling CGH Arrays

Greisman

Hoffman

2011

The Journal of Molecular Diagnostics

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The diagnosis and classification of many cancers depends in part on the identification of large-scale genomic aberrations such as chromosomal deletions, duplications, and balanced translocations. Arraybased comparative genomic hybridization (array CGH) can detect chromosomal imbalances on a genome-wide scale but cannot reliably identify balanced chromosomal rearrangements. We describe a simple modification of array CGH that enables simultaneous identification of recurrent balanced rearrangements and genomic imbalances on the same microarray. Using custom tiling oligonucleotide arrays and genespecific linear amplification primers, translocation CGH (tCGH) maps balanced rearrangements to ϳ100-base resolution and facilitates the rapid cloning and sequencing of novel rearrangement breakpoints. As proof of principle, we used tCGH to characterize nine of the most common gene fusions in mature B-cell neoplasms and myeloid leukemias. Because tCGH can be performed in any CGH-capable laboratory and can screen for multiple recurrent translocations and genome-wide imbalances, it should be of broad utility in the diagnosis and classification of various types of lymphomas, leukemias, and solid tumors. ( J Mol Diagn

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“…2,3 However, the increased availability of commercial IGH probes, along with advances in molecular and cytogenetic techniques, has led to the identification of several recurrent translocations involving IGH in B-ALL. 3 These translocations result in deregulated expression of the partner gene, presumably because of the resulting proximity to enhancer elements within the IGH locus. 4 Recently, a small number of cases of B-ALL involving IGH and the erythropoietin receptor gene (EPOR) at 19p13.1 have been reported.…”

mentioning

confidence: 99%