In Vivo Eradication of Human BCR/ABL-Positive Leukemia Cells With an ABL Kinase Inhibitor

Coutre, Philipp le; Mologni, Luca; Cleris, Loredana; Marchesi, Edoardo; Buchdunger, Elisabeth; Giardini, Roberto; Formelli, Franca; Gambacorti‐Passerini, Carlo

doi:10.1093/jnci/91.2.163

Cited by 334 publications

(200 citation statements)

References 11 publications

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“…Gleevec treatment produced a complete inhibition of tumor growth, indicating that a continuous block of Gleevec targets activity is needed to produce complete tumor regression. Similar results were observed when Gleevec was administered every 8 h in mice bearing Leydig cell tumors (Basciani et al, 2005) and in nude mice bearing Bcr/Abl-positive human leukemia cell lines (le Coutre et al, 1999). Discontinuation of Gleevec treatment resulted in rapid tumor re-growth, confirming the need for a sustained blockage of Gleevec targets to inhibit tumorigenesis.…”

Section: Discussionsupporting

confidence: 71%

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Kit and PDGFR-α activities are necessary for Notch4/Int3-induced tumorigenesis

et al. 2006

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Transgenic mice overexpressing Notch4 intracellular domain (Int3) under the control of the whey acidic protein (WAP) or mouse mammary tumor virus-long terminal repeat promoters, develop mammary tumors. Microarray analysis of these tumors revealed high levels of c-Kit expression. Gleevec is a tyrosine kinase inhibitor that targets c-Kit, platelet-derived growth factor receptors (PDGFRs) and c-Abl. This led us to speculate that tyrosine kinase receptor activity might be a driving force in the development of Int3 mammary tumors. WAP-Int3 tumor-bearing mice were treated with continuous release of Gleevec using subcutaneously implanted Alzet pumps. Phoshorylation of c-Kit, PDGFRs and c-Abl is inhibited in Int3 transgenic mammary tumors by Gleevec. Inhibition of these enzymes is associated with a decrease in cell proliferation and angiogenesis, and an induction of apoptosis. To examine the signaling mechanisms underlying Notch4/Int3 tumorigenesis, we employed small interfering RNA (siRNA) to knock down c-Kit, PDGFRs and c-Abl alone or in combination and observed the effects on soft agar growth of HC11 cells overexpressing Int3. Only siRNA constructs for c-Kit and/or PDGFR-a were able to inhibit HC11-Int3 colony formation in soft agar. Our data demonstrate an inhibitory effect of Gleevec on Int3-induced transformation of HC11 cells and mammary tumors and indicate an oncogenic role for c-Kit and PDGFR-a tyrosine kinases in the context of Int3 signaling.

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Section: Discussionsupporting

confidence: 71%

“…The length, width and depth of palpable tumors were measured with Vernier calipers. TW was determined using the equation TW (mg) ¼ (S) 2 Â L/2 where S and L (le Coutre et al, 1999) were measured in millimeters. S and L are the shortest and longest diameters of the tumor, respectively.…”

Section: Animals and Experimental Designmentioning

confidence: 99%

Kit and PDGFR-α activities are necessary for Notch4/Int3-induced tumorigenesis

et al. 2006

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“…It is interesting to note that bcr/abl constitute targets to the development of selective tyrosine kinase inhibitors. The avaibility of such inhibitors able to block bcr/abl tyrosine kinase constitutes a promising approach to the treatment of CML (Druker and Lydon, 2000; Lecoutre et al, 1999). Whether such compounds could reverse the constitutive activation of gc/Jak3 in leukemic progenitors should be determined.…”

Section: Discussionmentioning

confidence: 99%

Altered natural killer cell differentiation in CD34+ progenitors from Chronic Myeloid Leukemia patients

et al. 2000

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IL-15 and SCF fail to induce NK di erentiation and proliferation of CD34 + hematopoietic progenitors from chronic myeloid leukemia patients in contrast to normal stem cells although, both normal and leukemic CD34 + cells display comparable expression of c-kit or IL-15 receptor subunits. Interestingly, confocal microscopy analysis revealed that leukemic and most normal CD34 + cells produce and secrete IL-15, as shown by its tra cking through the Golgi apparatus and early endosomes. However, only leukemic progenitors express the membrane bound IL-15. Colocalization and internalization of IL-15Rb/gc and IL-15Ra/gc complexes indicated that IL-15 was speci®cally uptaken by leukemic progenitors. We also demonstrated that in both normal and leukemic progenitors, the signaling kinase Jak3 is constitutively pre-associated with the gc chain. Anti-IL-15 neutralizing mAb treatment resulted in downregulation of gc chain and disruption of gc/Jak3 interaction in normal but had no e ect in leukemic progenitors. Our results suggest the existence in both normal and leukemic CD34 + cells of a constitutive production of a bioactive IL-15 that does not lead to NK di erentiation and further indicate that membrane bound IL-15 and constitutive activation of gc are hallmarks of leukemic progenitors.

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“…In many cancers, specific drugs are indicated for specific subtypes of cancer. Herceptin is only effective to the subpopulation of individuals with breast cancer who express ERBB2 (McNeil, 1998), and Gleevec is for individuals with chronic myeloid leukemia resulting from the BCR-ABL1 gene fusion (le Coutre et al, 1999). Similarly, two recent studies identified mutations in EGFR in lung adenocarcinomas, which predict response to the tyrosine kinase inhibitor gefitinib (Lynch et al, 2004;Paez et al, Figure 2 Comparative functional genomics.…”

Section: Comparative Functional Genomicsmentioning

confidence: 99%

Comparative and integrative functional genomics of HCC

2006

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Global gene expression profiling of hepatocellular carcinoma (HCC) is a promising new technology that has already refined the diagnosis and prognostic predictions of HCC patients. This has been accomplished by identifying genes whose expression pattern is associated with clinicopathological features of HCC tumors. Molecular characterization of HCC from gene expression profiling studies will undoubtedly improve the prediction of treatment responses, selection of treatments for specific molecular subtypes of HCC and ultimately the clinical outcome of HCC patients. The research focus is now shifting toward the identification of genetic determinants that are components of the specific regulatory pathways altered in cancers, and that may constitute novel therapeutic targets. Here we review the recent advances in gene expression profiling of HCC and discuss the future strategies for analysing large and complicated data sets from microarray studies and how to integrate these with diverse genomic data.

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In Vivo Eradication of Human BCR/ABL-Positive Leukemia Cells With an ABL Kinase Inhibitor

Abstract: These data indicate that the continuous block of the oncogenic tyrosine kinase of Bcr/Abl protein is needed to produce important biologic effects in vivo.

Cited by 334 publications

References 11 publications

Kit and PDGFR-α activities are necessary for Notch4/Int3-induced tumorigenesis

Kit and PDGFR-α activities are necessary for Notch4/Int3-induced tumorigenesis

Altered natural killer cell differentiation in CD34+ progenitors from Chronic Myeloid Leukemia patients

Comparative and integrative functional genomics of HCC

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