New Insights into the Pathophysiology of Chronic Myeloid Leukemia and Imatinib Resistance

Kantarjian, Hagop M.; Talpaz, Moshe; Giles, Francis J.; O’Brien, Susan; Cortés, Jorge E.

doi:10.7326/0003-4819-145-12-200612190-00008

Cited by 228 publications

(167 citation statements)

References 88 publications

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“…Such resistance involves a variety of cellular mechanisms, including mutations of the bcr-abl gene, amplification of the bcr-abl gene locus, and activation of downstream signaling elements, such as Src-kinase-dependent pathways (19,(23)(24)(25)(26)(27)(28). Research efforts aimed to overcome development of imatinib resistance have led to the development of the second generation BCR-ABL tyrosine kinase inhibitors that include nilotinib (AMN-107) and dasatinib, both of which are active against various BCR-ABL kinase mutations associated with refractoriness to imatinib mesylate (29,(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42).…”

Section: Chronic Myeloid Leukemia (Cml)mentioning

confidence: 99%

Suppression of Programmed Cell Death 4 (PDCD4) Protein Expression by BCR-ABL-regulated Engagement of the mTOR/p70 S6 Kinase Pathway

Carayol

Katsoulidis

Sassano

et al. 2008

Journal of Biological Chemistry

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There is accumulating evidence that mammalian target of rapamycin (mTOR)-activated pathways play important roles in cell growth and survival of BCR-ABL-transformed cells. We have previously shown that the mTOR/p70 S6 kinase (p70 S6K) pathway is constitutively activated in BCR-ABL transformed cells and that inhibition of BCR-ABL kinase activity by imatinib mesylate abrogates such activation. We now provide evidence for the existence of a novel regulatory mechanism by which BCR-ABL promotes cell proliferation, involving p70 S6K-mediated suppression of expression of programmed cell death 4 (PDCD4), a tumor suppressor protein that acts as an inhibitor of cap-dependent translation by blocking the translation initiation factor eIF4A. Our data also establish that second generation BCR-ABL kinase inhibitors block activation of p70 S6K and downstream engagement of the S6 ribosomal protein in BCR-ABL transformed cells. Moreover, PDCD4 protein expression is up-regulated by inhibition of the BCR-ABL kinase in K562 cells and BaF3/BCR-ABL transfectants, suggesting a mechanism for the generation of the proapoptotic effects of such inhibitors. Knockdown of PDCD4 expression results in reversal of the suppressive effects of nilotinib and imatinib mesylate on leukemic progenitor colony formation, suggesting an important role for this protein in the generation of antileukemic responses. Altogether, our studies identify a novel mechanism by which BCR-ABL may promote leukemic cell growth, involving sequential engagement of the mTOR/p70 S6K pathway and downstream suppression of PDCD4 expression. Chronic myeloid leukemia (CML)2 is a clonal myeloproliferative disorder, whose hallmark is the presence of the BCR-ABL oncoprotein, which results from the abnormal bcr-abl fusion oncogene (1-3). bcr-abl is created by a reciprocal translocation involving chromosomes 9 and 22, and its abnormal protein product plays a key and essential role in the pathogenesis of CML (1-4). The constitutive tyrosine kinase activity of BCR-ABL mediates phosphorylation of multiple downstream substrates and engagement of various mitogenic pathways that promote cell growth and survival (1-7). The introduction of imatinib mesylate in the management of chronic myelogenous leukemia has had a dramatic impact on the natural history of the disease (reviewed in Refs. 8 -11). This agent induces long lasting hematologic and cytogenetic responses in patients with early and late phase CML (8, 12, 13, 14, 16 -18) by its ability to block activation the BCR-ABL kinase and generation of mitogenic responses (8 -11).Although the introduction of imatinib mesylate was a major breakthrough in the management of CML, there has been emerging evidence for resistance to its antileukemic properties in vitro and in vivo (19 -22). Such resistance involves a variety of cellular mechanisms, including mutations of the bcr-abl gene, amplification of the bcr-abl gene locus, and activation of downstream signaling elements, such as Src-kinase-dependent pathways (19,(23)(24)(25)(26)(27)(28). Research ...

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Section: Chronic Myeloid Leukemia (Cml)mentioning

confidence: 99%

Suppression of Programmed Cell Death 4 (PDCD4) Protein Expression by BCR-ABL-regulated Engagement of the mTOR/p70 S6 Kinase Pathway

Carayol

Katsoulidis

Sassano

et al. 2008

Journal of Biological Chemistry

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“…1,2 Approximately two-thirds of patients progress to BP via AP with a median survival for patients in AP of 1 to 2 years. 1,3 Although the mechanisms behind progression to advanced phase disease in CML have not been fully elucidated, several processes may play a role, including additional cytogenetic abnormalities (clonal evolution), genetic mutations and deletions, and up-regulation of specific genes.…”

Section: Introductionmentioning

confidence: 99%

Phase 3 study of dasatinib 140 mg once daily versus 70 mg twice daily in patients with chronic myeloid leukemia in accelerated phase resistant or intolerant to imatinib: 15-month median follow-up

Kantarjian

Cortes

Kim³

et al. 2009

Blood

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151

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Dasatinib is the most potent BCR-ABL inhibitor, with 325-fold higher potency than imatinib against unmutated BCR-ABL in vitro. Studies have demonstrated the benefits of dasatinib 70 mg twice daily in patients with acceleratedphase chronic myeloid leukemia intolerant or resistant to imatinib. A phase 3 study compared the efficacy and safety of dasatinib 140 mg once daily with the current twice-daily regimen. Here, results from the subgroup with acceleratedphase chronic myeloid leukemia (n ‫؍‬ 317) with a median follow-up of 15 months (treatment duration, 0.03-31.15 months) are reported. Among patients randomized to once-daily (n ‫؍‬ 158) or twice-daily (n ‫؍‬ 159) treatment, rates of major hematologic and cytogenetic responses were comparable (major hematologic response, 66% vs 68%; major cytogenetic response, 39% vs 43%, respectively). Estimated progression-free survival rates at 24 months were 51% and 55%, whereas overall survival rates were 63% versus 72%. Once-daily treatment was associated with an improved safety profile. In particular, significantly fewer patients in the once-daily group experienced a pleural effusion (all grades, 20% vs 39% P < .001). These results demonstrate that dasatinib 140 mg once daily has similar efficacy to dasatinib 70 mg twice daily but with an improved safety profile. This trial is registered at www. IntroductionChronic myeloid leukemia (CML) is characterized by a triphasic natural course comprising a chronic phase (CP), typically followed by an accelerated phase (AP), and finally a blast phase (BP). 1,2 Approximately two-thirds of patients progress to BP via AP with a median survival for patients in AP of 1 to 2 years. 1,3 Although the mechanisms behind progression to advanced phase disease in CML have not been fully elucidated, several processes may play a role, including additional cytogenetic abnormalities (clonal evolution), genetic mutations and deletions, and up-regulation of specific genes. [3][4][5][6] Current first-line therapy for AP-CML is imatinib mesylate (Glivec [in the United States, Gleevec]; Novartis, Basel, Switzerland), an oral tyrosine kinase inhibitor of BCR-ABL. 7-9 Although imatinib induces notable hematologic and cytogenetic responses in patients with accelerated-phase chronic myeloid leukemia (CML-AP), these responses are frequently short-lived, with a median progression-free survival (PFS) of 8.8 months. 7 Development of resistance to imatinib represents an important clinical issue affecting approximately 50% of patients with CML-AP within 2 years of treatment. 10 Because progression on imatinib is associated with poor prognosis, 11 alternative treatment options are required.Dasatinib (SPRYCEL; Bristol-Myers Squibb, Stamford, CT) was the first agent approved to overcome the problems of imatinib therapy in patients with CML. Dasatinib is structurally unrelated to imatinib and is approximately 325-fold more potent than imatinib at inhibiting unmutated BCR-ABL in vitro. 12 Preclinical studies have also shown that dasatinib has potent activity against ot...

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“…A Bcr-abl protein of 210 kDa is observed in more than 90% of CML and 30%-35% of acute lymphocytic leukemia (ALL) patients. Bcr-abl proteins of 190 and 230 kDa are detected in ALL and chronic neutrophilic leukemia patients, respectively (Chan at al., 1987;Deininger et al, 2000;Kantarjian at al., 2006;Quintás-Cardama and Cortes, 2009). Bcr-abl tyrosine kinase activity causes malignant cell transformation.…”

Section: Introductionmentioning

confidence: 99%

Multidrug resistance in chronic myeloid leukemia

Unlu¹,

Kiraz²,

Kaci³

et al. 2014

Turk J Biol

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Chronic myeloid leukemia (CML) is characterized by the accumulation of Philadelphia chromosome-positive (Ph+) myeloid cells. Ph+ cells occur via a reciprocal translocation between the long arms of chromosomes 9 and 22 resulting in constitutively active Bcr-abl fusion protein. Tyrosine kinase inhibitors (TKIs) are used against the kinase activity of Bcr-abl fusion protein for the effective treatment of CML. However, the development of drug resistance, directed by different genetic mechanisms, is the major problem of clinical applications of TKIs. These mechanisms include mutations in the TKI binding site of Bcr-abl, overexpression of Bcr-abl, overexpression of ATP binding cassette transporters, aberrant ceramide metabolism, inhibition of apoptosis, and changes in expression levels of microRNAs. Recently, many studies have focused on understanding the molecular mechanisms of drug resistance in cancer while targeting therapies providing reversal of resistance. Cancer stem cells also have roles in tumor initiation, maintenance, progression, metastasis, and drug resistance. Uncovering the mechanisms of drug resistance can provide more efficient treatment of cancer since these findings may provide novel targets for a complete cure. In this review, we discuss recent findings on the mechanisms of multidrug resistance and its reversal in CML. © TÜBİTAK

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New Insights into the Pathophysiology of Chronic Myeloid Leukemia and Imatinib Resistance

Cited by 228 publications

References 88 publications

Suppression of Programmed Cell Death 4 (PDCD4) Protein Expression by BCR-ABL-regulated Engagement of the mTOR/p70 S6 Kinase Pathway

Suppression of Programmed Cell Death 4 (PDCD4) Protein Expression by BCR-ABL-regulated Engagement of the mTOR/p70 S6 Kinase Pathway

Phase 3 study of dasatinib 140 mg once daily versus 70 mg twice daily in patients with chronic myeloid leukemia in accelerated phase resistant or intolerant to imatinib: 15-month median follow-up

Multidrug resistance in chronic myeloid leukemia

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