Exome sequencing identifies mutation in CNOT3 and ribosomal genes RPL5 and RPL10 in T-cell acute lymphoblastic leukemia

Keersmaecker, Kim De; Atak, Zeynep Kalender; Li, Ning; Vicente, Carmen; Patchett, Stephanie; Girardi, Tiziana; Gianfelici, Valentina; Geerdens, Ellen; Clappier, Emmanuelle; Porcu, Michaël; Lahortiga, Idoya; Lucà, Rossella; Yan, Jiekun; Hulselmans, Gert; Vranckx, Hilde; Vandepoel, Roel; Sweron, Bram; Jacobs, Kris; Mentens, Nele; Włodarska, Iwona; Cauwelier, Bárbara; Cloos, Jacqueline; Soulier, Jean; Uyttebroeck, Anne; Bagni, Claudia; Hassan, Bassem A.; Vandenberghe, Peter; Johnson, Arlen; Aerts, Stein; Cools, Jan

doi:10.1038/ng.2508

Cited by 378 publications

(425 citation statements)

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“…Consistent with previous genomic studies (26,38), pediatric ALL leukemia samples in our series showed a low burden of exonic mutations and copy number alterations at diagnosis. Moreover, and with the exception of one T-ALL tumor, which showed a marked increase in mutation load at relapse, the mutation load of these leukemias was only modestly increased at relapse.…”

Section: Discussionsupporting

confidence: 78%

“…S1 and S2 and Datasets S3 and S4). Recurrently somatically mutated genes in our series included known oncogenes and tumor suppressors mutated in B-cell precursor ALL [KRAS, NRAS, Fms related tyrosine kinase 3 (FLT3), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and CREBBP] (20) and T-cell ALL [Notch1 (NOTCH1), FBXW7, PHF6, DNM2, WT1, JAK1, JAK3, BCL11B, TP53, CREBBP, RPL10, RUNX1, and CNOT3] (16,(21)(22)(23)(24)(25)(26)(27). In addition, we also identified recurrently ALL mutated genes including ZFHX3, ubiquitin specific peptidase 9, X-linked (USP9X), calcium voltage-gated channel subunit alpha1 H (CACNA1H), EPHA3, SHROOM3, USP7, RPGR, 5-hydroxytryptamine receptor 3A (HTR3A), mediator complex subunit 12 (MED12), teneurin transmembrane protein 3 (TENM3), and IL17RA (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Mutational landscape, clonal evolution patterns, and role of RAS mutations in relapsed acute lymphoblastic leukemia

Oshima

Khiabanian

Silva-Almeida

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

156

115

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Although multiagent combination chemotherapy is curative in a significant fraction of childhood acute lymphoblastic leukemia (ALL) patients, 20% of cases relapse and most die because of chemorefractory disease. Here we used whole-exome and whole-genome sequencing to analyze the mutational landscape at relapse in pediatric ALL cases. These analyses identified numerous relapse-associated mutated genes intertwined in chemotherapy resistance-related protein complexes. In this context, RAS-MAPK pathway-activating mutations in the neuroblastoma RAS viral oncogene homolog (NRAS), kirsten rat sarcoma viral oncogene homolog (KRAS), and protein tyrosine phosphatase, nonreceptor type 11 (PTPN11) genes were present in 24 of 55 (44%) cases in our series. Interestingly, some leukemias showed retention or emergence of RAS mutant clones at relapse, whereas in others RAS mutant clones present at diagnosis were replaced by RAS wildtype populations, supporting a role for both positive and negative selection evolutionary pressures in clonal evolution of RAS-mutant leukemia. Consistently, functional dissection of mouse and human wild-type and mutant RAS isogenic leukemia cells demonstrated induction of methotrexate resistance but also improved the response to vincristine in mutant RAS-expressing lymphoblasts. These results highlight the central role of chemotherapy-driven selection as a central mechanism of leukemia clonal evolution in relapsed ALL, and demonstrate a previously unrecognized dual role of RAS mutations as drivers of both sensitivity and resistance to chemotherapy.acute lymphoblastic leukemia | relapsed leukemia | chemotherapy resistance | genome sequencing A cute lymphoblastic leukemia (ALL) is the most common malignancy in children (1-4). Current therapy of pediatric newly diagnosed ALL includes initial clearance of leukemic lymphoblasts with cytotoxic drugs and glucocorticoids followed by delivery of chemotherapy to the central nervous system and a prolonged lower intensity maintenance treatment phase aimed at securing long-term remission by reducing the rates of leukemia relapse (3). Altogether 95% of pediatric ALL patients achieve a complete hematologic remission during induction and 80% of them remain leukemia free (5). However, the prognosis of patients showing refractory disease or those whose leukemia relapses after an initial transient response remains disappointingly poor, with cure rates of less than 40% (6, 7). Several mechanisms have been implicated as drivers of leukemia relapse, including the presence of rare quiescent and intrinsically chemoresistant leukemia stem cells with increased self-renewal capacity (8), protection from chemotherapy by safe-haven microenvironment niches (9, 10), and selection of secondary genetic alterations promoting chemotherapy resistance in leukemic lymphoblasts (11)(12)(13). In this regard, early studies described the presence of tumor protein p53 (TP53) mutations in relapsed ALL, supporting a role for escape from genotoxic stress in leukemia progression (14). Similarly, lo...

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Section: Discussionsupporting

confidence: 78%

Section: Resultsmentioning

confidence: 99%

Mutational landscape, clonal evolution patterns, and role of RAS mutations in relapsed acute lymphoblastic leukemia

Oshima

Khiabanian

Silva-Almeida

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

156

115

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“…This appears to be of importance in human T-acute lymphocyte leukemia (ALL), a childhood tumor more common in males than in females and a corresponding experimental model of the disease [112][113][114] . Additional X-linked players altered in T-ALL are the PHF6 and RPL10 genes, which are mutated almost exclusively in male patients 115,116 . Loss-of-function UTX mutations have also been found in oesophageal SCCs and renal cell carcinomas, which are more frequent in the male population 117,118 .…”

Section: A) X Chromosomementioning

confidence: 99%

Sexual dimorphism in cancer

et al. 2016

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The incidence of many cancer types is significantly higher in the male than female populations, with associated differences in survival. Occupational and/or behavioral factors are well known underlying determinants. However, cellular/molecular differences between the two sexes are also likely to be important. We are focusing here on the complex interplay that sexual hormones and sex chromosomes can have in intrinsic control of cancer initiating cell populations, tumor microenvironment and systemic determinants of cancer development like the immune system and metabolism. A better appreciation of these differences between the two sexes could be of substantial value for cancer prevention as well as treatment.3 Introduction (Epidemiology)

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“…Over the last decade, studies utilizing microarray analysis of gene expression, DNA copy-number alterations, and next-generation sequencing have provided major insights into the pathogenesis and clinical behavior of ALL. [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] Most ALL genomes harbor sequence and structural DNA alterations involving coding genes, as well as alterations of noncoding elements such as noncoding RNAs 23 and enhancer elements. 24,25 Here, we consider results from these studies in several categories: (1) identification of new subtypes of ALL that lack recurring gross chromosomal alterations; (2) characterization of the constellations of genetic alterations that define each ALL subtype; (3) the relationship between genetic alterations, clonal heterogeneity, and relapse; (4) identification of inherited genetic variants and mutations linked to ALL susceptibility and outcome; (5) and translating new discoveries to improved diagnostic, prognostic, and precision medicine approaches.…”

Section: Introductionmentioning

confidence: 99%

Redefining ALL classification: toward detecting high-risk ALL and implementing precision medicine

Hunger

Mullighan

2015

Blood

252

198

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Acute lymphoblastic leukemia (ALL) is the commonest childhood tumor and remains a leading cause of cancer death in the young. In the last decade, microarray and sequencing analysis of large ALL cohorts has revolutionized our understanding of the genetic basis of this disease. These studies have identified new ALL subtypes, each characterized by constellations of structural and sequence alterations that perturb key cellular pathways, including lymphoid development, cell-cycle regulation, and tumor suppression; cytokine receptor, kinase, and Ras signaling; and chromatin modifications. Several of these pathways, particularly kinase-activating lesions and epigenetic alterations, are logical targets for new precision medicine therapies. Genomic profiling has also identified important interactions between inherited genetic variants that influence the risk of leukemia development and the somatic genetic alterations that are required to establish the leukemic clone. Moreover, sequential sequencing studies at diagnosis, remission, and relapse have provided important insights into the relationship among genetic variants, clonal heterogeneity, and the risk of relapse. Ongoing studies are extending our understanding of coding and noncoding genetic alterations in B-progenitor and T-lineage ALL and using these insights to inform the development of faithful experimental models to test the efficacy of new treatment approaches. (Blood. 2015;125(26):3977-3987)

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Exome sequencing identifies mutation in CNOT3 and ribosomal genes RPL5 and RPL10 in T-cell acute lymphoblastic leukemia

Cited by 378 publications

References 54 publications

Mutational landscape, clonal evolution patterns, and role of RAS mutations in relapsed acute lymphoblastic leukemia

Mutational landscape, clonal evolution patterns, and role of RAS mutations in relapsed acute lymphoblastic leukemia

Sexual dimorphism in cancer

Redefining ALL classification: toward detecting high-risk ALL and implementing precision medicine

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