Pharmacological inhibition of c-Abl compromises genetic stability and DNA repair in Bcr-Abl-negative cells

Fanta, Silke; Sonnenberg, Maike; Skorta, Ioanna; Duyster, Justus; Miething, Cornelius; Aulitzky, Walter E.; Kuip, Heiko van der

doi:10.1038/onc.2008.68

Cited by 19 publications

(16 citation statements)

References 27 publications

(22 reference statements)

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“…The presence of a nucleotide change in the germ line ABL sequence should rather evoke a polymorphism. Cell genetic instability after longterm inhibition of ABL by TKI could be an explanation [32], although we have no direct demonstration of this event.…”

Section: Discussionmentioning

confidence: 97%

Extensive analysis of the T315I substitution and detection of additional ABL mutations in progenitors and primitive stem cell compartment in a patient with tyrosine kinase inhibitor-resistant chronic myeloid leukemia

Chomel

Sorel²,

Bonnet

et al. 2010

Leukemia & Lymphoma

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Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML). However, resistance is occasionally observed, mainly due to mutations within the BCR-ABL kinase domain. The T315I substitution confers complete resistance to all TKIs commonly used in clinical practice. To date, the hierarchical level of stem cells in which this mutation initially appears has not been studied. The aim of this study was to evaluate the behavior of T315I mutated cells and to study the presence of potential additional mutations in progenitors and stem cells from a patient with CML. A comprehensive analysis of BCR-ABL(315I) mRNA expressing cells in mononuclear cells, in CD34+ cell populations, and in their primitive long-term culture-initiating cell (LTC-IC) derived progenitors was performed. We show that the T315I substitution arises in primitive Ph1 stem cells without altering their myeloid and erythroid terminal differentiation potential. Leukemic cells expressing a T315I mutated BCR-ABL display a progressive decline in LTC-IC assays as described for non-mutated CML cells at diagnosis. Finally, in our experiments, additional non-315 ABL mutations were identified in hematopoietic stem cell colonies. This observation is suggestive of genetic instability affecting CML progenitors.

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Section: Discussionmentioning

confidence: 97%

Extensive analysis of the T315I substitution and detection of additional ABL mutations in progenitors and primitive stem cell compartment in a patient with tyrosine kinase inhibitor-resistant chronic myeloid leukemia

Chomel

Sorel²,

Bonnet

et al. 2010

Leukemia & Lymphoma

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“…An implication of this study is that clinical use of Abl kinase inhibitor STI571 in chronic myelogenous leukemia treatment might compromise cell response to DNA damage in the patients, leading to accumulation of more secondary mutations. [35][36][37] In addition to positively regulating Atm/Atr activation, our study shows that c-Abl might have an important role in regulating foci formation of proteins like 53BP1, TopBP1, Rad51, and Brca1. This might not be attributable to compromised Atm/Atr activation as Atm/Atr deficiency or inhibition usually leads to a decrease in foci formation of these proteins.…”

Section: Discussionmentioning

confidence: 99%

A positive role for c-Abl in Atm and Atr activation in DNA damage response

et al. 2010

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DNA damage triggers Atm-and/or Atr-dependent signaling pathways to control cell cycle progression, apoptosis, and DNA repair. However, how Atm and Atr are activated is not fully understood. One of the downstream targets of Atm is non-receptor tyrosine kinase c-Abl, which is phosphorylated and activated by Atm. The current view is that c-Abl relays pro-apoptotic signals from Atm to p73 and p53. Here we show that c-Abl deficiency resulted in a broad spectrum of defects in cell response to genotoxic stress, including activation of Chk1 and Chk2, activation of p53, nuclear foci formation, apoptosis, and DNA repair, suggesting that c-Abl might also act upstream of the DNA damage-activated signaling cascades in addition to its role in p73 and p53 regulation. Indeed, we found that c-Abl is required for proper activation of both Atm and Atr. c-Abl is bound to the chromatin and shows enhanced interaction with Atm and Atr in response to DNA damage. c-Abl can phosphorylate Atr on Y291 and Y310 and this phosphorylation appears to have a positive role in Atr activation under genotoxic stress. These findings suggest that Atm-mediated c-Abl activation in cell response to double-stranded DNA breaks might facilitate the activation of both Atm and Atr to regulate their downstream cellular events. Cell Death and Differentiation (2011) 18, 5-15; doi:10.1038/cdd.2010; published online 27 August 2010 DNA damage can be caused by exogenous or endogenous factors such as ionizing radiation (IR), chemotherapeutic drugs, and stalled replication forks. 1 It is believed that various DNA lesions are eventually converted to double-stranded breaks (DSBs) and/or single-stranded DNA (ssDNA or SSBs), where sensors, mediators, transducers, and effectors assemble to form nuclear foci, which function as centers of signal propagation. At the core of the signaling network are PI-3 kinase-like kinases (PIKKs), including Atm, Atr and DNA-PKcs. 2 Atm is mainly activated by DSBs, whereas Atr responds to various DNA lesions. 3 Atm and Atr are recruited to the nuclear foci by the MRN (Mre11-Rad50-NBS) complex and ATRIP, respectively, 4,5 where they phosphorylate proteins such as p53, Chk1, Chk2, and H2AX, to activate cell cycle checkpoints and/or induce apoptosis. 6 Phosphorylation of Chk1 and Chk2 by Atr and Atm is facilitated by a group of nuclear foci proteins called mediators, for example, Brca1, TopBP1, and 53BP1. Furthermore, the nuclear foci also function as repair centers. 7 DSB repair is believed to involve an Atm to Atr switch. 8,9 Atm is first recruited to DSBs and ssDNA is later generated by resection of the DNA ends, where Atr can be assembled and activated. Thus, there exists a complex functional interaction between these two PIKKs. 10 Although several proteins have been reported to activate Atm or Atr, 11,12 the initial activation of Atm/Atr and the regulation of their activities in the process of DNA repair are poorly understood. 13,14 The c-Abl proto-oncogene encodes a non-receptor tyrosine kinase that is essential for perinatal survival in ...

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“…Therefore, most patients remain Bcr-Abl + . Furthermore, therapy with imatinib may select the emergency of resistance and impair genomic stability in Bcr-Abl − cells (22,23). Moreover, therapy results of imatinib are less impressive in accelerated disease and Philadelphia chromosome-positive (Ph + ) acute lymphoblastic leukemia (ALL; ref.…”

Section: Introductionmentioning

confidence: 99%

Imatinib Mesylate Induces Cisplatin Hypersensitivity in Bcr-Abl+ Cells by Differential Modulation of p53 Transcriptional and Proapoptotic Activity

et al. 2009

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Imatinib is highly effective in inducing remission in chronic myelogenous leukemia (CML). However, complete eradication of the malignant clone by imatinib is rare. We investigated the efficacy of combining imatinib with cisplatin. Inhibition of Bcr-Abl by imatinib induced a hypersensitive phenotype both in Bcr-Abl + cell lines and in CD34 + cells from CML patients. Importantly, cisplatin sensitivity of leukemic cells harboring an inactive Bcr-Abl greatly exceeded that of Bcr-Abl − parental cells. The cisplatin response of Bcr-Abl + cells treated with imatinib was characterized by an impaired G 2 -M arrest and by rapid induction of mitochondrial cell death after the first passage through G 2 . Imatinib abrogated ATM activation on cisplatin selectively in Bcr-Abl + cells. As a consequence, phosphorylation of p53 on Ser 15 and its activity as a transcription factor was significantly diminished. Furthermore, p53 accumulated predominantly in the cytoplasm in Bcr-Abl + cells treated with imatinib and cisplatin. Silencing of p53 significantly reduced sensitivity to cisplatin in imatinib-treated Bcr-Abl + cells, indicating that p53 retains its proapoptotic activity. Simultaneous downregulation of Bcl-x L was an additional requirement for cisplatin hypersensitivity, as p53-dependent cell death could be antagonized by exogenous Bcl-x L . We conclude that imatinib sensitizes Bcr-Abl + cells to cisplatin by simultaneous inhibition of p53 transactivation, induction of p53 accumulation predominantly in the cytoplasm, and reduction of Bcl-x L . [Cancer Res 2009;69(24):9337-45]

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Pharmacological inhibition of c-Abl compromises genetic stability and DNA repair in Bcr-Abl-negative cells

Cited by 19 publications

References 27 publications

Extensive analysis of the T315I substitution and detection of additional ABL mutations in progenitors and primitive stem cell compartment in a patient with tyrosine kinase inhibitor-resistant chronic myeloid leukemia

Extensive analysis of the T315I substitution and detection of additional ABL mutations in progenitors and primitive stem cell compartment in a patient with tyrosine kinase inhibitor-resistant chronic myeloid leukemia

A positive role for c-Abl in Atm and Atr activation in DNA damage response

Imatinib Mesylate Induces Cisplatin Hypersensitivity in Bcr-Abl+ Cells by Differential Modulation of p53 Transcriptional and Proapoptotic Activity

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