Imatinib therapy in chronic myelogenous leukemia: strategies to avoid and overcome resistance

Hochhaus, Andreas; Rosée, Paul La

doi:10.1038/sj.leu.2403426

Cited by 308 publications

(207 citation statements)

References 101 publications

(133 reference statements)

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“…The mechanism behind the observed drop of mutated BCR-ABL upon imatinib interruption might be based on a suppression of the mutated clone by the reapparent wild type. 25 These cases are of importance for the clinical management of PLoop-mutated and imatinib-resistant patients. 4 The interaction between wild-type and mutated clone could be exploited as a therapeutic option.…”

Section: Discussionmentioning

confidence: 99%

Selecting and deselecting imatinib-resistant clones: observations made by longitudinal, quantitative monitoring of mutated BCR-ABL

et al. 2005

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Resistance to imatinib during the treatment of chronic myeloid leukaemia (CML) is frequently associated with point mutations in the ABL gene encoding the ATP binding region likely to cause disease relapse. Early diagnosis and monitoring of these mutations may be important in order to prevent rapid expansion of resistant clones. We describe a quantitative mutationspecific PCR assay based on the readily available Taqman platform. Selectivity for the mutated target is conferred by mutation-specific primers destabilised by additional mismatches. The assay can be carried out in parallel to standard BCR-ABL quantification and is therefore more quickly compared to standard sequencing procedures. The sensitivity of the assay reaches 0.1%. It also allows for quantitative assessment of mutated clones. By analysing sequential samples of resistant subjects, we show how mutated clones were selected, maintained or deselected depending on the individual treatment setting. The high sensitivity and practical merits of this method makes it a good candidate for prospective molecular surveillance of patients at high risk for imatinib resistance.

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Section: Discussionmentioning

confidence: 99%

Selecting and deselecting imatinib-resistant clones: observations made by longitudinal, quantitative monitoring of mutated BCR-ABL

et al. 2005

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“…Moreover, in various human and mouse models, hematopoietic cells expressing BCR-ABL show a growth advantage, resistance to apoptosis and altered adhesion and homing properties. In clinical research, tyrosine kinase inhibitors targeting BCR-ABL have dramatically improved the therapeutic outcomes of patients with CML (Gorre et al, 2001;Shah et al, 2002;Corbin et al, 2003;Gambacorti-Passerini et al, 2003b;Lowenberg, 2003;Hochhaus and La Rosee, 2004). For instance, the agent imatinib mesylate led to a large number of cytogenic and molecular responses in CML patients, resulting in greatly prolonged survival.…”

Section: Introductionmentioning

confidence: 99%

STAP-2 interacts with and modulates BCR-ABL-mediated tumorigenesis

et al. 2012

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In chronic myeloid leukemia (CML), the BCR-ABL fusion oncoprotein activates multiple pathways involved in cell survival, growth promotion and disease progression. In this report, we show that the signal transducing adaptor protein-2 (STAP-2) is involved in BCR-ABL activity. We demonstrate that STAP-2 bound to BCR-ABL, and BCR and ABL proteins, depending on the STAP-2 Src homology 2-like domain. BCR-ABL phosphorylates STAP-2 Tyr250 and the phosphorylated STAP-2 in turn up-regulated BCR-ABL phosphorylation, leading to enhanced activation of downstream signaling molecules including ERK, STAT5, BCL-xL and BCL-2. In addition, STAP-2 interacts with BCR-ABL to alter chemokine receptor expression leading to downregulation of CXCR4 and upregulation of CCR7. The interaction between STAP-2 and BCR-ABL plays a crucial role in conferring a growth advantage and resistance to imatinib, a BCR-ABL inhibitor, as well as tumor progression. Notably, mice injected with BCR-ABL/STAP-2-expressing Ba/F3 cells developed lymph node enlargement and hepatosplenomegaly. Moreover, suppression of STAP-2 in K562 CML cells resulted in no tumor formation in mice. Our results demonstrate a critical contribution of STAP-2 in BCR-ABL activity, and suggest that STAP-2 might be an important candidate for drug development for patients with CML. Further, the expression of STAP-2 provides useful information for estimating the characteristics of individual CML clones

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“…Two types of resistance mechanisms to TKIs have been described: 1) Primary resistance, which occurs in less than 10% of cases and is defined as the failure of therapeutic effect during the chronic phase of CML without changing clones; and 2) secondary resistance, defined as the loss of the response initially obtained, and commonly occurs in accelerated phase (40-50%) and blast (80%) [90] It is estimated that the probability of an individual to stay in CCR for 5 years after diagnosis, after treatment with Imatinib is approximately 63%; however, this percentage may represent a sub-estimation since in a significant proportion of cases there is discontinuation of treatment and this, of course, may underestimate the efficacy of the drug [91].…”

Section: Stem Cell Biology In Normal Life and Diseasesmentioning

confidence: 99%