Imatinib mesylate (STI571) inhibits growth of primitive malignant progenitors in chronic myelogenous leukemia through reversal of abnormally increased proliferation

Abstract

IntroductionChronic myelogenous leukemia (CML) is a hematopoietic stem cell malignant disease 1 that arises from a reciprocal translocation between chromosomes 9 and 22. 2 It is characterized by a massive expansion of myeloid progenitors as well as more differentiated cells originating from the malignant clone. The disease progresses from an initial chronic phase through an accelerated phase followed by an inevitable acute leukemia or blast crisis as the malignant cells lose their ability to differentiate. The translocation (9;22)(q34;q11) fuses a truncated BCR gene (chromosome 9) to sequences upstream of the second exon of ABL (chromosome 22). The resulting fusion gene encodes a protein tyrosine kinase, Bcr-Abl, with more elevated and disregulated activity compared with c-abl. Expression of Bcr-Abl in mice was found to induce a CML-like myeloproliferative disorder, [3][4][5][6][7] indicating that Bcr-Abl plays a key role in leukemic transformation. Additional studies have shown that the tyrosine kinase activity is critical to the transforming ability of 7,8 making it an attractive target for drug development.Imatinib mesylate (STI571; formerly CGP571418B; Gleevec; Novartis Pharmaceuticals, East Hanover, NJ) is a 2-phenylaminopyrimidine derivative developed as a potent inhibitor of the Abl protein tyrosine kinases (v-Abl, Bcr-Abl, and c-Abl). 9,10 It also has activity against the platelet-derived growth-factor receptor (PDGF-R), 10 c-Kit, 11 ARG, 12 and their fusion proteins, Tel-Abl and Tel-PDGF-R, 13 but does not affect other kinases.Phase I and phase II clinical trials of imatinib mesylate in the treatment of chronic-phase CML showed that it is well tolerated, with few adverse effects. 14 Complete hematologic responses and cytogenetic responses, including complete cytogenetic responses, were reported in a significant proportion of patients. Activity against more advanced accelerated and blast-crisis phases of CML was also observed. 15 Imatinib mesylate is currently approved for the treatment of patients with chronic-phase CML in whom interferon therapy has failed and for accelerated-phase and blast-crisis disease. However, the durability of responses to imatinib mesylate, the agent's impact on long-term survival and normal hematopoiesis, and its role in the treatment of CML compared with other modalities remain unclear.In vitro studies have shown that imatinib mesylate inhibits growth of cell lines expressing Bcr-Abl. 10,13,16,17 Additionally, the numbers of colony-forming cells (CFCs) in peripheral blood or bone marrow from patients with CML have been found to be The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 U.S.C. section 1734. For personal use only. on May 9, 2018. by guest www.bloodjournal.org From reduced, with minimal inhibition of normal cells. 10,17 One study showed that imatinib mesylate inhibited the enhanced replating ability of granulocyte-macroph...

Apoptosis-based dual molecular targeting by INNO-406, a second-generation Bcr-Abl inhibitor, and ABT-737, an inhibitor of antiapoptotic Bcl-2 proteins, against Bcr-Abl-positive leukemia

“…29,30 Furthermore, Bcr-Abl inhibitors have been shown to be more cytostatic than cytotoxic against Bcr-Abl þ leukemic cells. 9,10 These suggest that the complete eradication of Bcr-Abl þ leukemic cells may require Bcr-Abl inhibitors in combination with therapies that modify the molecular pathways that control cell survival. Our study supports this premise, as we were able to markedly increase the killing of transcriptional activator of bim.…”

“…19 Besides sensitizing to apoptosis, ABT-737 may be also expected to eradicate Bcr-Abl þ LSCs those may escape the killing by Bcr-Abl inhibitors. 9,10 How does the dual targeting of Bcr-Abl and antiapoptotic Bcl-2 proteins synergize in eradicating Bcr-Abl þ leukemias? To maintain and expand the tumor, leukemic cells need to maintain their capacity for cell proliferation, while being resistant to apoptosis in the face of cytotoxic or environmental insults.…”

“…7,8 However, it appears that a few leukemic cells often survive exposure to imatinib or second-generation Bcr-Abl inhibitors. 9,10 Indeed, mathematical modeling studies suggest that complete eradication of Bcr-Abl þ leukemic cells may require simultaneous targeting of other vital molecules. 11,12 Here, we have sought to identify additional therapeutic targets by characterizing the molecular mechanism by which the blockade of Bcr-Abl signaling kills Ph þ leukemia cells.…”

Somatic stem cells and the origin of cancer

“…Indeed, recent data suggest that imatinib may not achieve complete ablation of CML cells 217 , and even patients with CML who present complete molecular response almost invariably relapse when the drug is discontinued 216,218 . These observations may be explained by in vitro findings suggesting that ima- tinib, which is very active against differentiated CML progenitors, shows limited activity against CML stem cells [219][220][221] . Unequivocal in vivo proof of the resistance of leukemic stem cells to imatinib was recently provided by Sanchez-Garcia et al 222 .…”

Antibody-based detection of protein phosphorylation status to track the efficacy of novel therapies using nanogram protein quantities from stem cells and cell lines

“…Nonetheless second and third generation TKIs have been developed in response to BCR-ABL mutations inferring resistance to treatment (for review see O'Hare 21 ). Despite continued TKI therapy in CML patients, the minimal effect of TKIs on primitive CML haemopoietic cells results in the persistence of minimal residual disease (MDR) which causes disease relapse upon drug withdrawal [22][23][24][25][26][27] . Given that CML is a stem-cell-driven disease, any new potentially curative therapies must be tested on primary stem cells, which are only available in finite quantities.…”