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CBL, CBLB, TET2, ASXL1, and IDH1/2 mutations and additional chromosomal aberrations constitute molecular events in chronic myelogenous leukemia.

ABSTRACT: Progression of chronic myelogenous leukemia (CML) to accelerated (AP) and blast phase (BP) is because of secondary molecular events, as well as additional cytogenetic abnormalities. On the basis of the detection of JAK2, CBL, CBLB, TET2, ASXL1, and IDH1/2 mutations in myelodysplastic/myeloproliferative neoplasms, we hypothesized that they may also contribute to progression in CML. We screened these genes for mutations in 54 cases with CML (14 with chronic phase, 14 with AP, 20 with myeloid, and 6 with nonmyeloid BP). We identified 1 CBLB and 2 TET2 mutations in AP, and 1 CBL, 1 CBLB, 4 TET2, 2 ASXL1, and 2 IDH family mutations in myeloid BP. However, none of these mutations were found in chronic phase. No cases with JAK2V617F mutations were found. In 2 cases, TET2 mutations were found concomitant with CBLB mutations. By single nucleotide polymorphism arrays, uniparental disomy on chromosome 5q, 8q, 11p, and 17p was found in AP and BP but not involving 4q24 (TET2) or 11q23 (CBL). Microdeletions on chromosomes 17q11.2 and 21q22.12 involved tumor associated genes NF1 and RUNX1, respectively. Our results indicate that CBL family, TET2, ASXL1, and IDH family mutations and additional cryptic karyotypic abnormalities can occur in advanced phase CML.

SUBMITTER: Makishima H

PROVIDER: S-EPMC3110035 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:T-cell receptor (TCR) signaling is essential for the function of T cells and negatively regulated by the E3 ubiquitin-protein ligases CBL and CBLB. Here we combine mouse genetics and affinity purification coupled to quantitative mass spectrometry to monitor the dynamics of the CBL and CBLB signaling complexes that assemble in normal T cells over 600 seconds of TCR stimulation. We identify many previously known CBL and CBLB interacting partners, as well as a majority of proteins that have not yet been implicated in those signaling complexes. We exploit correlations in protein association with CBL and CBLB as a function of time of TCR stimulation for predicting the occurrence of direct physical association between them. The dataset is divided in two distinct subsets corresponding to the Cbl and to the Cblb interactomes. Each of them contains mass spectrometry results from the analysis of 10 different conditions of AP-MS purifications (based on affinity purification on Streptactin beads of One-Strep-tagged proteins) starting from CD4+ T cells which were either non stimulated or stimulated with anti-CD3 and anti-CD4 antibodies as follows: CBL interactome: - CBL-OST transgenic mice, CD4+ T cells non stimulated (noted Cbl_0) - CBL-OST transgenic mice, CD4+ T cells stimulated 30s (noted Cbl_30) - CBL-OST transgenic mice, CD4+ T cells stimulated 120s (noted Cbl_120) - CBL-OST transgenic mice, CD4+ T cells stimulated 300s (noted Cbl_300) - CBL-OST transgenic mice, CD4+ T cells stimulated 600s (noted Cbl_600) - WT mice, CD4+ T cells non stimulated (noted WT_0) - WT mice, CD4+ T cells stimulated 30s (noted WT_30) - WT mice, CD4+ T cells stimulated 120s (noted WT_120) - WT mice, CD4+ T cells stimulated 300s (noted WT_300) - WT mice, CD4+ T cells stimulated 600s (noted WT_600) For the CBL interactome, 3 biological replicates were prepared for these 10 different conditions (noted Ech1, Ech2, Ech3), yielding 30 analyzed samples. Three technical nanoLC-MS runs were acquired for each sample (noted R1, R2, R3), leading to 90 nanoLC-MS raw files. CBL interactome: - CBLB-OST transgenic mice, CD4+ T cells non stimulated (noted Cblb_0) - CBLB-OST transgenic mice, CD4+ T cells stimulated 30s (noted Cblb_30) - CBLB-OST transgenic mice, CD4+ T cells stimulated 120s (noted Cblb_120) - CBLB-OST transgenic mice, CD4+ T cells stimulated 300s (noted Cblb_300) - CBL-OST transgenic mice, CD4+ T cells stimulated 600s (noted Cblb_600) - WT mice, CD4+ T cells non stimulated (noted WT_0) - WT mice, CD4+ T cells stimulated 30s (noted WT_30) - WT mice, CD4+ T cells stimulated 120s (noted WT_120) - WT mice, CD4+ T cells stimulated 300s (noted WT_300) - WT mice, CD4+ T cells stimulated 600s (noted WT_600) For the CBLB interactome, 4 biological replicates were prepared for these 10 different conditions (noted S1, S2, S3, S4), yielding 40 analyzed samples. For series S1 to S3, 2 technical nanoLC-MS runs were acquired for each sample (noted R1, R2) and for serie S4, 3 technical nanoLC-MS runs were acquired for each sample (noted R1, R2, R3), leading in total to 90 nanoLC-MS raw files.

Project description:BackgroundAdditional chromosomal aberrations in Philadelphia chromosome-positive chronic myeloid leukemia are non-random and strongly associated with disease progression, but their prognostic impact and effect on treatment response is not clear. Point mutations in the BCR-ABL kinase domain are probably the most common mechanisms of imatinib resistance.Design and methodsWe assessed the influence of additional chromosomal aberrations and BCR-ABL kinase domain mutations on the response to the second-generation tyrosine kinase inhibitor nilotinib after imatinib-failure. Standard cytogenetic analysis of metaphases was performed to detect additional chromosomal aberrations and the BCR-ABL kinase domain was sequenced to detect point mutations.ResultsAmong 53 patients with a median follow-up of 16 months, of whom 38, 5 and 10 were in chronic phase, accelerated phase and blast crisis, respectively, 19 (36%) had additional chromosomal aberrations and 20 (38%) had BCR-ABL kinase domain mutations. The 2-year overall survival rate of all patients with-out additional chromosomal aberrations (89%) was higher than that of patients with such aberrations (54%) (P=0.0025). Among patients with chronic phase disease, overall survival at 2 years was 100% and 62% for patients without or with additional chromosomal aberrations, respectively (P=0.0024). BCR-ABL kinase domain mutations were associated with lower remission rates in response to nilotinib, with 9 of 20 (45%) of these patients achieving a major cytogenetic remission as compared to 26 of 33 (79%) patients without mutations (P<0.05). However, overall survival was not affected by BCR-ABL kinase domain mutations.ConclusionsWhereas BCR-ABL kinase domain mutations may confer more specific resistance to nilotinib, which will predominantly affect response rates, the presence of additional chromosomal aberrations may reflect genetic instability and, therefore, intrinsic aggressiveness of the disease which will be less amenable to subsequent alternative treatments and thus negatively affect overall survival. Conventional cytogenetic analyses remain mandatory during follow-up of patients with chronic myeloid leukemia under tyrosine kinase inhibitor therapy.

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CBL, CBLB, TET2, ASXL1, and IDH1/2 mutations and additional chromosomal aberrations constitute molecular events in chronic myelogenous leukemia.

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