The development of imatinib as a therapeutic agent for chronic myeloid leukemia

Deininger, Michael W.; Buchdunger, Elisabeth; Druker, Brian J.

doi:10.1182/blood-2004-08-3097

Cited by 1,143 publications

(864 citation statements)

References 134 publications

(96 reference statements)

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“…Finally, the expression of bcl 2 , bcl x and bax was reasonably similar in these cell lines as was the expression of c-Jun and c-Fos, and the upstream kinases JNK1 and JNK2 ( Figure 2d). Interferon has been used to treat patients, but has recently been replaced by the tyrosine kinase inhibitor imatinib (Deininger et al, 2005). Growth inhibition by imatinib was also unchanged in junB D/D cells (data not shown).…”

Section: Resultsmentioning

confidence: 94%

JunB is a gatekeeper for B-lymphoid leukemia

et al. 2007

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Loss of JunB has been observed in human leukemia and lymphoma, but it remains unknown, whether this loss is relevant to disease progression. Here, we investigated the consequences of JunB deficiency using Abelson-induced B-lymphoid leukemia as a model system. Mice deficient in JunB expression succumbed to Abelson-induced leukemia with increased incidence and significantly reduced latency. Similarly, bcr/abl p185-transformed JunB-deficient (junB D/D ) cells induced leukemia in RAG2 À/À mice displaying a more malignant phenotype. These observations indicated that cell intrinsic effects within the junB D/D tumor cells accounted for the accelerated leukemia development. Indeed, explantated bcr/abl p185 transformed junB D/D cells proliferated faster than the control cells. The proliferative advantage emerged slowly after the initial transformation process and was associated with increased expression levels of the cell cycle kinase cdk6 and with decreased levels of the cell cycle inhibitor p16 INK4a . These alterations were due to irreversible reprogramming of the cell, because -once established -accelerated disease induced by junB D/D cells was not reverted by re-introducing JunB. Consistent with this observation, we found that the p16 promoter was methylated. Thus, JunB functions as a gatekeeper during tumor evolution. In its absence, transformed leukemic cells acquire an enhanced proliferative capacity, which presages a more malignant disease.

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Section: Resultsmentioning

confidence: 94%

JunB is a gatekeeper for B-lymphoid leukemia

et al. 2007

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“…In particular, T670I is homologous to T315I of BCR-ABL detected in some CML patients resistant to imatinib (Deininger et al, 2005). As they affect the ATP pocket of the kinases, it could be supposed that other molecules could be employed as alternative drugs in a second-line therapy in both the diseases, GIST and CML.…”

Section: Molecular Modelingmentioning

confidence: 99%

Functional analyses and molecular modeling of two c-Kit mutations responsible for imatinib secondary resistance in GIST patients

et al. 2006

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Imatinib-acquired resistance related to the presence of secondary point mutations has become a frequent event in gastrointestinal stromal tumors. Here, transient transfection experiments with plasmids carrying two different KIT-acquired point mutations were performed along with immunoprecipitation of total protein extracts, derived from imatinib-treated and untreated cells. The molecular mechanics/Poisson Boltzmann surface area computational techniques were applied to study the interactions of the wild-type and mutated receptors with imatinib at the molecular level. Biochemical analyses showed KIT phosphorylation in cells transfected with vectors carrying the specific mutant genes. Imatinib treatment demonstrated that T670I was insensitive to the drug at all the applied concentrations, whereas V654A was inhibited by 6 lM of imatinib. The modeling of the mutated receptors revealed that both substitutions affect imatinib-binding site, but to a different extent: T670I substantially modifies the binding pocket, whereas V654A induces only relatively confined structural changes. We demonstrated that T670I and V654A cause indeed imatinib-acquired resistance and that the former is more resistant to imatinib than the latter. The application of molecular simulations allowed us to quantify the interactions between the mutated receptors and imatinib, and to propose a molecular rationale for this type of drug resistance.

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“…Imatinib mesylate (Gleevec, Novartis Basel, Switzerland; STI571), a Kit, Abl and PDGFR inhibitor, induces apoptosis of the Ph 1 CML progenitors by suppressing the ability of BCR/ABL to phosphorylate substrates through competitive inhibition at the BCR/ABL ATP binding site (Druker et al, 1996). The development of the BCR/ABL tyrosine kinase inhibitor imatinib mesylate (Gleevec; formerly STI571) as the treatment of choice for chronic phase CML and its remarkable therapeutic effects suggest that blast crisis transition will be postponed for several years in the majority of CML patients (Deininger et al, 2005a;Roy et al, 2006). However, the persistence of BCR/ABL transcripts in a cohort of patients with complete cytogenetic response (Hughes et al, 2003) and the resistance of the primitive CML stem cell to imatinib treatment (Copland et al, 2006) raises the possibility that treatment with imatinib alone might delay but not prevent disease progression.…”

Section: CML Bcr/abl and Imatinibmentioning

confidence: 99%

“…However, the persistence of BCR/ABL transcripts in a cohort of patients with complete cytogenetic response (Hughes et al, 2003) and the resistance of the primitive CML stem cell to imatinib treatment (Copland et al, 2006) raises the possibility that treatment with imatinib alone might delay but not prevent disease progression. Furthermore, most of the CML patients in the accelerated and blastic phases of the disease are either refractory or develop resistance to imatinib monotherapy (Deininger et al, 2005a). In these CML-BC patients, imatinib resistance often depends on reactivation of BCR/ABL tyrosine kinase activity via mechanisms involving BCR/ABL overexpression, gene amplification or mutations that suppress imatinibmediated kinase inhibition (i.e.…”

Section: CML Bcr/abl and Imatinibmentioning

confidence: 99%

ReSETting PP2A tumour suppressor activity in blast crisis and imatinib-resistant chronic myelogenous leukaemia

Perrotti

Neviani

2006

Br J Cancer

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The deregulated kinase activity of p210-BCR/ABL oncoproteins, hallmark of chronic myelogenous leukaemia (CML), induces and sustains the leukaemic phenotype, and contributes to disease progression. Imatinib mesylate, a BCR/ABL kinase inhibitor, is effective in most of chronic phase CML patients. However, a significant percentage of CML patients develop resistance to imatinib and/or still progresses to blast crisis, a disease stage that is often refractory to imatinib therapy. Furthermore, there is compelling evidence indicating that the CML leukaemia stem cell is also resistant to imatinib. Thus, there is still a need for new drugs that, if combined with imatinib, will decrease the rate of relapse, fully overcome imatinib resistance and prevent blastic transformation of CML. We recently reported that the activity of the tumour suppressor protein phosphatase 2A (PP2A) is markedly inhibited in blast crisis CML patient cells and that molecular or pharmacologic re-activation of PP2A phosphatase led to growth suppression, enhanced apoptosis, impaired clonogenic potential and decreased in vivo leukaemogenesis of imatinib-sensitive and -resistant (T315I included) CML-BC patient cells and/or BCR/ABL þ myeloid progenitor cell lines. Thus, the combination of PP2A phosphatase-activating and BCR/ABL kinase-inhibiting drugs may represent a powerful therapeutic strategy for blast crisis CML patients.

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The development of imatinib as a therapeutic agent for chronic myeloid leukemia

Abstract: Imatinib has revolutionized drug therapy of chronic myeloid leukemia (CML).

Cited by 1,143 publications

References 134 publications

JunB is a gatekeeper for B-lymphoid leukemia

JunB is a gatekeeper for B-lymphoid leukemia

Functional analyses and molecular modeling of two c-Kit mutations responsible for imatinib secondary resistance in GIST patients

ReSETting PP2A tumour suppressor activity in blast crisis and imatinib-resistant chronic myelogenous leukaemia

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