Transposon Mutagenesis Reveals Fludarabine Resistance Mechanisms in Chronic Lymphocytic Leukemia

Pandzic, Tatjana; Larsson, Jimmy; He, Liqun; Kundu, Snehangshu; Ban, Kenneth; Akhtar-Ali, Muhammad; Hellström, Anders R.; Schuh, Anna; Clifford, Ruth; Blakemore, Stuart J.; Strefford, Jonathan C.; Baumann, Tycho; López‐Guillermo, Armando; Campo, Elı́as; Ljungström, Viktor; Mansouri, Larry; Rosenquist, Richard; Sjöblom, Tobias; Hellström, Mats

doi:10.1158/1078-0432.ccr-15-2903

Cited by 27 publications

(25 citation statements)

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“…The literature suggests that patients with MAPK-ERK mutations represent a biologically distinct subgroup, where MAPK-ERK mutations are frequently mutually exclusive, are enriched for trisomy 12, unmutated IGHV genes and other adverse biological markers (e.g. CD38, ZAP-70, CD49d), and are linked to inferior time to first treatment in retrospective cohorts [41,[43][44][45]. We now show the MAPK-ERK genes, BRAF, KRAS and NRAS (collectively representing 12.2% of patients) are also independently associated with short OS in a cohort of patients requiring treatment.…”

Section: Discussionmentioning

confidence: 99%

Clinical significance of TP53, BIRC3, ATM and MAPK-ERK genes in chronic lymphocytic leukaemia: data from the randomised UK LRF CLL4 trial

et al. 2020

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Despite advances in chronic lymphocytic leukaemia (CLL) treatment, globally chemotherapy remains a central treatment modality, with chemotherapy trials representing an invaluable resource to explore disease-related/genetic features contributing to long-term outcomes. In 499 LRF CLL4 cases, a trial with >12 years follow-up, we employed targeted resequencing of 22 genes, identifying 623 mutations. After background mutation rate correction, 11/22 genes were recurrently mutated at frequencies between 3.6% (NFKBIE) and 24% (SF3B1). Mutations beyond Sanger resolution (<12% VAF) were observed in all genes, with KRAS mutations principally composed of these low VAF variants. Firstly, employing orthogonal approaches to confirm <12% VAF TP53 mutations, we assessed the clinical impact of TP53 clonal architecture. Whilst ≥ 12% VAF TP53mut cases were associated with reduced PFS and OS, we could not demonstrate a difference between <12% VAF TP53 mutations and either wild type or ≥12% VAF TP53mut cases. Secondly, we identified biallelic BIRC3 lesions (mutation and deletion) as an independent marker of inferior PFS and OS. Finally, we observed that mutated MAPK-ERK genes were independent markers of poor OS in multivariate survival analysis. In conclusion, our study supports using targeted resequencing of expanded gene panels to elucidate the prognostic impact of gene mutations.

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Section: Discussionmentioning

confidence: 99%

Clinical significance of TP53, BIRC3, ATM and MAPK-ERK genes in chronic lymphocytic leukaemia: data from the randomised UK LRF CLL4 trial

et al. 2020

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“…DDR1 gene is highly expressed in various cancer types, such as in chronic lymphocytic leukaemia (Barisione et al, 2017). In addition, BMP2K gene has been recently shown to be implicated in chronic lymphocytic leukemia (CLL) (Pandzic et al, 2016), while CHST11 has long been known to be deregulated in CLL (Schmidt et al, 2004). TNFSF11 encodes RANKL which is part of a prominent cancer signalling pathway (Renema et al, 2016) and TNFSF11 has been reported to be the most overexpressed gene in a sample of n = 129 acute lymphoblastic leukemia (ALL) patients (Heltemes-Harris et al, 2011).…”

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Toward Explainable Anticancer Compound Sensitivity Prediction via Multimodal Attention-Based Convolutional Encoders

et al. 2019

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“…In several studies, this method also has been used to characterize resistance mechanisms in vitro (17)(18)(19) and in mice…”

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Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf ^−/− mouse model

Chapeau

Gembarska

Durand

et al. 2017

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

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Inhibitors of double minute 2 protein (MDM2)-tumor protein 53 (TP53) interaction are predicted to be effective in tumors in which the TP53 gene is wild type, by preventing TP53 protein degradation. One such setting is represented by the frequent CDKN2A deletion in human cancer that, through inactivation of p14ARF, activates MDM2 protein, which in turn degrades TP53 tumor suppressor. Here we used piggyBac (PB) transposon insertional mutagenesis to anticipate resistance mechanisms occurring during treatment with the MDM2-TP53 inhibitor HDM201. Constitutive PB mutagenesis in Arf −/− mice provided a collection of spontaneous tumors with characterized insertional genetic landscapes. Tumors were allografted in large cohorts of mice to assess the pharmacologic effects of HDM201. Sixteen out of 21 allograft models were sensitive to HDM201 but ultimately relapsed under treatment. A comparison of tumors with acquired resistance to HDM201 and untreated tumors identified 87 genes that were differentially and significantly targeted by the PB transposon. Resistant tumors displayed a complex clonality pattern suggesting the emergence of several resistant subclones. Among the most frequent alterations conferring resistance, we observed somatic and insertional loss-of-function mutations in transformation-related protein 53 (Trp53) in 54% of tumors and transposonmediated gain-of-function alterations in B-cell lymphoma-extra large (Bcl-xL), Mdm4, and two TP53 family members, resulting in expression of the TP53 dominant negative truncations ΔNTrp63 and ΔNTrp73. Enhanced BCL-xL and MDM4 protein expression was confirmed in resistant tumors, as well as in HDM201-resistant patient-derived tumor xenografts. Interestingly, concomitant inhibition of MDM2 and BCL-xL demonstrated significant synergy in p53 wild-type cell lines in vitro. Collectively, our findings identify several potential mechanisms by which TP53 wild-type tumors may escape MDM2-targeted therapy.drug resistance | MDM2 inhibitor | piggyBac screen | cancer A mong the genes most commonly altered in human cancer, regardless of tumor type, are tumor protein 53 (TP53) tumor suppressor (1) and CDKN2A (INK4a/ARF) (2). The latter gene encodes two tumor suppressor proteins: p16INK4a (3), an inhibitor of cyclin D-dependent kinases that, at least in part, regulates the function of the retinoblastoma protein (RB), and p19ARF (4), a negative regulator of double minute 2 protein (MDM2) function that activates TP53, thereby inducing cell cycle arrest or apoptosis. TP53 protein levels are regulated through MDM2-mediated degradation.Toward the goal of reactivating TP53 in cells harboring inactivating upstream pathway alterations, compounds inhibiting the interaction between MDM2 and TP53, preventing TP53 degradation, have been discovered. Such agents induce TP53 reactivation in tumors in which the TP53 gene is wild type (5-8).Although preclinical studies of such MDM2 inhibitors have demonstrated significant antitumor activity, tumors commonly relapse (9, 10).Rapid emergence of resistance is...

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Transposon Mutagenesis Reveals Fludarabine Resistance Mechanisms in Chronic Lymphocytic Leukemia

Cited by 27 publications

References 60 publications

Clinical significance of TP53, BIRC3, ATM and MAPK-ERK genes in chronic lymphocytic leukaemia: data from the randomised UK LRF CLL4 trial

Clinical significance of TP53, BIRC3, ATM and MAPK-ERK genes in chronic lymphocytic leukaemia: data from the randomised UK LRF CLL4 trial

Toward Explainable Anticancer Compound Sensitivity Prediction via Multimodal Attention-Based Convolutional Encoders

Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf ^−/− mouse model

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Transposon Mutagenesis Reveals Fludarabine Resistance Mechanisms in Chronic Lymphocytic Leukemia

Cited by 27 publications

References 60 publications

Clinical significance of TP53, BIRC3, ATM and MAPK-ERK genes in chronic lymphocytic leukaemia: data from the randomised UK LRF CLL4 trial

Clinical significance of TP53, BIRC3, ATM and MAPK-ERK genes in chronic lymphocytic leukaemia: data from the randomised UK LRF CLL4 trial

Toward Explainable Anticancer Compound Sensitivity Prediction via Multimodal Attention-Based Convolutional Encoders

Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf −/− mouse model

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Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf ^−/− mouse model