Exome sequencing reveals DNMT3A and ASXL1 variants associate with progression of chronic myeloid leukemia after tyrosine kinase inhibitor therapy

Kim, TaeHyung; Tyndel, Marc S.; Zhang, Zhaolei; Ahn, Jae‐Sook; Choi, Seung-Hyun; Szardenings, Michael; Lipton, Jeffrey H.; Kim, Hyeoung-Joon; Hwan, Dennis Kim Dong

doi:10.1016/j.leukres.2017.06.009

Cited by 29 publications

(21 citation statements)

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“…The data from 15 studies of patients at diagnosis and 20 studies at AP/BC are reported where cancer genes were mutated in more than one patient at diagnosis and/or BC. [14,[20][21][22][23][24][25][26][27][28][29][30][31][32][42][43][44][45][46][47][48][49][50][51]] Some variants were not included, such as the ASXL1 E1102D variant, which is reported in the population databases at a frequency suggesting it represents the germline and is not pathogenic. Other variants reported in PAX5, TP53 and TET2 were also not included for the same reason.…”

Section: Resultsmentioning

confidence: 99%

“…[39][40][41] In the TKI era a number of studies have revealed mutations in other genes at varying frequencies in advanced phase patients ( Figure 1). [14,[20][21][22][23]30,31,[42][43][44][45][46][47][48][49][50][51] Once again, the analysis is focused on SNVs/indels in cancerassociated genes [33] and IKZF1 exon deletions. BCR-ABL1 kinase domain mutation status was only reported for 89 patients and were detected in 39%.…”

Section: Mutational Landscape At Advanced Phase CMLmentioning

confidence: 99%

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Laying the foundation for genomically-based risk assessment in chronic myeloid leukemia

et al. 2019

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Outcomes for patients with chronic myeloid leukemia (CML) have substantially improved due to advances in drug development and rational treatment intervention strategies. Despite these significant advances there are still unanswered questions on patient management regarding how to more reliably predict treatment failure at the time of diagnosis and how to select frontline tyrosine kinase inhibitor (TKI) therapy for optimal outcome. The BCR-ABL1 transcript level at diagnosis has no established prognostic impact and cannot guide frontline TKI selection. BCR-ABL1 mutations are detected in approximately 50% of TKI resistant patients but are rarely responsible for primary resistance. Other resistance mechanisms are largely uncharacterized and there are no other routine molecular testing strategies to facilitate the evaluation and further stratification of TKI resistance. Advances in next-generation sequencing technology has aided the management of a growing number of other malignancies, enabling the incorporation of somatic mutation profiles in diagnosis, classification and prognostication. A largely unexplored area in CML research is whether expanded genomic analysis at diagnosis, resistance and disease transformation can enhance patient management decisions, as has occurred for other cancers. The aim of this article is to review publications that reported mutated cancer-associated genes in CML patients at various disease phases. We discuss the frequency and type of such variants at initial diagnosis and at the time of treatment failure and transformation. Current limitations in the evaluation of mutants and recommendations for future reporting are outlined. The collective evaluation of mutational studies over more than a decade suggests a limited set of cancer-associated genes are indeed recurrently mutated in CML and some at a relatively high frequency. Genomic studies have the potential to lay the foundation for improved diagnostic risk classification according to clinical and genomic risk, and to enable more precise early identification of TKI resistance.

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Section: Resultsmentioning

confidence: 99%

Section: Mutational Landscape At Advanced Phase CMLmentioning

confidence: 99%

Laying the foundation for genomically-based risk assessment in chronic myeloid leukemia

et al. 2019

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“…It was shown that the resistance of leukemic cells is associated with the enhanced PI3K/AKT, RAF/MEK/ERK and STAT3 signaling pathways [29]. At the same time, studies involving patients with different responses to TKI, show influence of genetic polymorphisms in TKI metabolizers’ genes [9], BIM gene [30], FAS gene [10], DNMT3A and ASXL1 genes [11].…”

Section: Discussionmentioning

confidence: 99%

Exome, transcriptome and miRNA analysis don’t reveal any molecular markers of TKI efficacy in primary CML patients

Лавров¹,

Chelysheva

Адильгереева

et al. 2019

BMC Med Genomics

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BackgroundApproximately 5–20% of chronic myeloid leukemia (CML) patients demonstrate primary resistance or intolerance to imatinib. None of the existing predictive scores gives a good prognosis of TKI efficacy. Gene polymorphisms, expression and microRNAs are known to be involved in the pathogenesis of TKI resistance in CML. The aim of our study is to find new molecular markers of TKI therapy efficacy in CML patients.MethodsNewly diagnosed patients with Ph+ CML in chronic phase were included in this study. Optimal and non-optimal responses to TKI were estimated according to ELN 2013 recommendation. We performed genotyping of selected polymorphisms in 62 blood samples of CML patients, expression profiling of 33 RNA samples extracted from blood and miRNA profiling of 800 miRNA in 12 blood samples of CML patients.ResultsThe frequencies of genotypes at the studied loci did not differ between groups of patients with an optimal and non-optimal response to TKI therapy. Analysis of the expression of 34,681 genes revealed 26 differently expressed genes (p < 0.05) in groups of patients with different TKI responses, but differences were very small and were not confirmed by qPCR. Finally, we did not find difference in miRNA expression between the groups.ConclusionsUsing modern high-throughput methods such as whole-exome sequencing, transcriptome and miRNA analysis, we could not find reliable molecular markers for early prediction of TKI efficiency in Ph+ CML patients.Electronic supplementary materialThe online version of this article (10.1186/s12920-019-0481-z) contains supplementary material, which is available to authorized users.

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“…BCR-ABL1 kinase domain mutation-independent resistance is also associated with the presence of mutations in the epigenetic regulators ASXL1, DNMT3A, IDH1, and SETBP1 (Kim et al, 2017). Indeed, the presence of such mutations at the time of diagnosis is associated with an increased risk of poor treatment outcome (Branford et al, 2018) Furthermore, such mutations are also associated with progression to blast crisis (Giotopoulos et al, 2015;Grossmann et al, 2011).…”

Section: Bcr-abl1 Kinase Domain Mutation-independent Resistance Mechanismsmentioning

confidence: 99%

Response and Resistance to BCR-ABL1-Targeted Therapies

2020

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Chronic myeloid leukemia (CML), caused by constitutively active BCR-ABL1 fusion tyrosine kinase, has served as a paradigm for successful application of molecularly targeted cancer therapy. The development of the tyrosine kinase inhibitor (TKI) imatinib allows patients with CML to experience near-normal life expectancy. Specific point mutations that decrease drug binding affinity can produce TKI resistance, and secondand third-generation TKIs largely mitigate this problem. Some patients develop TKI resistance without known resistance mutations, with significant heterogeneity in the underlying mechanism, but this is relatively uncommon, with the majority of patients with chronic phase CML achieving long-term disease control. In contrast, responses to TKI treatment are short lived in advanced phases of the disease or in BCR-ABL1-positive acute lymphoblastic leukemia, with relapse driven by both BCR-ABL1 kinase-dependent and -independent mechanisms. Additionally, the frontline CML treatment with second-generation TKIs produces deeper molecular responses, driving disease burden below the detection limit for a greater number of patients. For patients with deep molecular responses, up to half have been able to discontinue therapy. Current efforts are focused on identifying therapeutic strategies to drive deeper molecular responses, enabling more patients to attempt TKI discontinuation.

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Exome sequencing reveals DNMT3A and ASXL1 variants associate with progression of chronic myeloid leukemia after tyrosine kinase inhibitor therapy

Cited by 29 publications

References 29 publications

Laying the foundation for genomically-based risk assessment in chronic myeloid leukemia

Laying the foundation for genomically-based risk assessment in chronic myeloid leukemia

Exome, transcriptome and miRNA analysis don’t reveal any molecular markers of TKI efficacy in primary CML patients

Response and Resistance to BCR-ABL1-Targeted Therapies

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