Towards personalized therapy in pediatric acute lymphoblastic leukemia: RAS mutations and prednisolone resistance

Ariës, Ingrid M.; Dungen, Rosanna E. van den; Koudijs, Marco J.; Cuppen, Edwin; Voest, Emile E.; Molenaar, Jan J.; Caron, Huib N.; Pieters, Rob; Boer, Monique L. den

doi:10.3324/haematol.2014.112995

Cited by 29 publications

(33 citation statements)

References 15 publications

(6 reference statements)

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“…High levels of AKT activity have been associated with steroid resistance and poor outcome in BCP-ALL [63]. Mutations in NRAS and KRAS are common in ALL and are associated with steroid resistance, central nervous system involvement, and poor outcome [16,17]; these mutations are preferentially acquired at relapse [18]. Connectivity mapping based on expression profiles of steroid-resistant ALL [64] suggests that mTOR inhibitors restore steroid sensitivity by reducing the levels of antiapoptotic MCL1 [65,66].…”

Section: Discussionmentioning

confidence: 99%

“…Activated NOTCH1 may confer steroid resistance by repressing expression of NR3C1 and PTEN [15]. Mutations in RAS have been shown to be associated with steroid resistance in BCP-ALL and are prevalent in relapsed patients [16–18]. Recently, CASP1 and its activator, NLRP3, were also shown to be associated with steroid resistance in ALL [19].…”

Section: Introductionmentioning

confidence: 99%

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IL-7 Receptor Mutations and Steroid Resistance in Pediatric T cell Acute Lymphoblastic Leukemia: A Genome Sequencing Study

et al. 2016

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BackgroundPediatric acute lymphoblastic leukemia (ALL) is the most common childhood cancer and the leading cause of cancer-related mortality in children. T cell ALL (T-ALL) represents about 15% of pediatric ALL cases and is considered a high-risk disease. T-ALL is often associated with resistance to treatment, including steroids, which are currently the cornerstone for treating ALL; moreover, initial steroid response strongly predicts survival and cure. However, the cellular mechanisms underlying steroid resistance in T-ALL patients are poorly understood. In this study, we combined various genomic datasets in order to identify candidate genetic mechanisms underlying steroid resistance in children undergoing T-ALL treatment.Methods and FindingsWe performed whole genome sequencing on paired pre-treatment (diagnostic) and post-treatment (remission) samples from 13 patients, and targeted exome sequencing of pre-treatment samples from 69 additional T-ALL patients. We then integrated mutation data with copy number data for 151 mutated genes, and this integrated dataset was tested for associations of mutations with clinical outcomes and in vitro drug response. Our analysis revealed that mutations in JAK1 and KRAS, two genes encoding components of the interleukin 7 receptor (IL7R) signaling pathway, were associated with steroid resistance and poor outcome. We then sequenced JAK1, KRAS, and other genes in this pathway, including IL7R, JAK3, NF1, NRAS, and AKT, in these 69 T-ALL patients and a further 77 T-ALL patients. We identified mutations in 32% (47/146) of patients, the majority of whom had a specific T-ALL subtype (early thymic progenitor ALL or TLX). Based on the outcomes of these patients and their prednisolone responsiveness measured in vitro, we then confirmed that these mutations were associated with both steroid resistance and poor outcome.To explore how these mutations in IL7R signaling pathway genes cause steroid resistance and subsequent poor outcome, we expressed wild-type and mutant IL7R signaling molecules in two steroid-sensitive T-ALL cell lines (SUPT1 and P12 Ichikawa cells) using inducible lentiviral expression constructs. We found that expressing mutant IL7R, JAK1, or NRAS, or wild-type NRAS or AKT, specifically induced steroid resistance without affecting sensitivity to vincristine or L-asparaginase. In contrast, wild-type IL7R, JAK1, and JAK3, as well as mutant JAK3 and mutant AKT, had no effect. We then performed a functional study to examine the mechanisms underlying steroid resistance and found that, rather than changing the steroid receptor’s ability to activate downstream targets, steroid resistance was associated with strong activation of MEK-ERK and AKT, downstream components of the IL7R signaling pathway, thereby inducing a robust antiapoptotic response by upregulating MCL1 and BCLXL expression. Both the MEK-ERK and AKT pathways also inactivate BIM, an essential molecule for steroid-induced cell death, and inhibit GSK3B, an important regulator of proapoptotic BIM. Importantly, treating our...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

IL-7 Receptor Mutations and Steroid Resistance in Pediatric T cell Acute Lymphoblastic Leukemia: A Genome Sequencing Study

et al. 2016

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“…The in vitro and in vivo evidence that NRAS-and KRAS-mutated clones were sensitive to the MEK inhibitors selumetinib and trametinib, provides a potential targeted therapy strategy for this subset of patients. 10,11 The outcome of patients with relapsed ALL remains unsatisfactory. Current risk stratification in BCP-ALL is based primarily on CR1 duration.…”

Section: -35mentioning

confidence: 99%

“…6,7 In contrast, cooperating or secondary aberrations are lost, enriched, or gained as the leukemia evolves under the selection pressure of frontline chemotherapy and the surviving subclones expand, resulting in relapse. [8][9][10][11] Several abnormalities are more prevalent at relapse (eg, TP53 12 and NR3C1 8,13 alterations). Recent studies suggest that some genetic abnormalities (eg, IKZF1, TP53, KRAS abnormalities) are prognostic biomarkers that can refine current risk stratification algorithms.…”

Section: Introductionmentioning

confidence: 99%

Integration of genetic and clinical risk factors improves prognostication in relapsed childhood B-cell precursor acute lymphoblastic leukemia

Irving

Enshaei

Parker

et al. 2016

Blood

109

111

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Key Points• Chromosomal abnormalities predict outcome after relapse in BCP-ALL, and high-risk cytogenetics takes precedence over clinical risk factors. • Patients with mutations or deletions targeting TP53, NR3C1, BTG1, and NRAS were associated with clinical high risk and an inferior outcome.Somatic genetic abnormalities are initiators and drivers of disease and have proven clinical utility at initial diagnosis. However, the genetic landscape and its clinical utility at relapse are less well understood and have not been studied comprehensively. We analyzed cytogenetic data from 427 children with relapsed B-cell precursor ALL treated on the international trial, ALLR3. Also we screened 238 patients with a marrow relapse for selected copy number alterations (CNAs) and mutations. Cytogenetic risk groups were predictive of outcome postrelapse and survival rates at 5 years for patients with good, intermediate-, and high-risk cytogenetics were 68%, 47%, and 26%, respectively (P < .001). TP53 alterations and NR3C1/BTG1 deletions were associated with a higher risk of progression: hazard ratio 2.36 (95% confidence interval, 1.51-3.70, P < .001) and 2.15 (1.32-3.48, P 5 .002). NRAS mutations were associated with an increased risk of progression among standard-risk patients with high hyperdiploidy: 3.17 (1.15-8.71, P 5 .026). Patients classified clinically as standard and high risk had distinct genetic profiles. The outcome of clinical standard-risk patients with high-risk cytogenetics was equivalent to clinical high-risk patients. Screening patients at relapse for key genetic abnormalities will enable the integration of genetic and clinical risk factors to improve patient stratification and outcome. This study is registered at www.clinicaltrials.org as #ISCRTN45724312. (Blood. 2016;128(7):911-922)

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“…Moreover, given that the therapeutic studies described above were performed in T-ALL models, evaluation of these findings in the context of B-ALL will also be important. Finally, RAS mutations have also previously been linked to prednisolone resistance (15) as well, and the MEK inhibitor trametinib was shown in at least one study to be synergistic with prednisolone (12,16).…”

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confidence: 99%

Genetic drivers of vulnerability and resistance in relapsed acute lymphoblastic leukemia

Abdel‐Wahab

2016

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

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Relapsed acute lymphoblastic leukemia (ALL) is associated with very poor outcomes despite modern therapies in both children and adults (1-3). In PNAS, Oshima et al. elucidate both the mutational landscape as well as patterns of clonal evolution of pediatric relapsed ALL and identify potential therapeutic targets in this challenging illness (4). Although prior studies have performed SNP array analysis (SNPa), wholeexome sequencing (WES), whole-genome sequencing (WGS), and/or mRNA sequencing (RNA-seq) at diagnosis and relapse (Table 1), the majority of prior analyses have focused on relapsed pediatric B-ALL specifically. Here, the authors performed WES of 55 pediatric ALL patients (33 T-cell ALL and 22 B-cell precursor ALL) at diagnosis, remission, and relapse and complemented these data with RNA-seq of a validation cohort of 49 paired diagnosis/relapse B-ALL patient samples. This analysis has allowed for reevaluation of the pattern of clonal evolution in relapsed ALL and revealed that the majority of relapsed ALLs (∼85%) contain only some of the genetic lesions present in the major clone at diagnosis. In contrast, only in 4% of cases did the relapsed clones contain all mutations present at diagnosis plus additional secondary relapse-specific lesions. Together, these data identify that linear evolution is rarely involved in tumor progression in ALL and that relapsed ALL originates primarily as derivatives of ancestral subclones related to, but distinct from the main leukemic population present at diagnosis. This conclusion extends previous observations of the clonal basis of relapsed ALL by Mullighan et al. (5), which used SNPa to reveal that cells responsible for relapse were often minor subpopulations of the cells responsible for initial disease (Table 1).In addition to evaluating the clonal basis of relapsed ALL, the authors identified several new genes enriched at relapse including ZFHX3, USP9X, CACNA1H, EPHA3, SHROOM3, USP7, RPGR, HTR3A, MED12, ODZ3, and IL17RA. Mutations associated with relapsed ALL appear to fall into several categories. First, there are mutations functionally related to the mechanism of action of chemotherapy used in initial treatment and/or previously linked to chemotherapy resistance. These include mutations in NT5C2, TP53, NR3C1, CREBBP, and MLL2. Ultradeep sequencing of diagnostic samples failed to identify these mutations in most cases, which suggests they were acquired at relapse and/or present in very small subclones at diagnosis. Given the need to develop novel targeted therapeutics for relapsed ALL, identification of therapeutically targetable genetic alterations enriched in relapse is critical. To this end, prior work from this group and others identified that mutations in the 5′-nucleotidase enzyme NT5C2 enhance inactivation of nucleoside-analog chemotherapeutic agents (6, 7). The frequency of NT5C2 mutations at relapse and the fact that NT5C2 mutations confer enhanced enzymatic activity argue for efforts to develop small-molecule inhibitors of mutant NT5C2.Mutations in CREBBP ...

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Towards personalized therapy in pediatric acute lymphoblastic leukemia: RAS mutations and prednisolone resistance

Cited by 29 publications

References 15 publications

IL-7 Receptor Mutations and Steroid Resistance in Pediatric T cell Acute Lymphoblastic Leukemia: A Genome Sequencing Study

IL-7 Receptor Mutations and Steroid Resistance in Pediatric T cell Acute Lymphoblastic Leukemia: A Genome Sequencing Study

Integration of genetic and clinical risk factors improves prognostication in relapsed childhood B-cell precursor acute lymphoblastic leukemia

Genetic drivers of vulnerability and resistance in relapsed acute lymphoblastic leukemia

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