Establishment and characterization of a novel imatinib‐sensitive chronic myeloid leukemia cell line MYL, and an imatinib‐resistant subline MYL‐R showing overexpression of Lyn

Ito, Takuo; Tanaka, Hideo; Kimura, Akiro

doi:10.1111/j.1600-0609.2007.00835.x

Cited by 37 publications

(55 citation statements)

References 45 publications

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“…Cell lines and reagents, and gene trasfection CML-derived BV173, KT-1, KCL22, K562 (Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH), KBM5 (13) and MYL (14) cell lines, Jurkat T cell, an immortalized T lymphocyte cell line, and HL60, Bcr-Abl-negative myelogenous leukemia cell line were maintained in RPMI 1640 with 10% FCS, 2 mmol/L L-glutamate, and penicillin/streptomycin. IM-resistant KBM5/IMR with Abl T315I mutation was generated by continuous culture in medium containing 1.0 μmol/L IM (15).…”

Section: Methodsmentioning

confidence: 99%

Targeting Activating Transcription Factor 3 by Galectin-9 Induces Apoptosis and Overcomes Various Types of Treatment Resistance in Chronic Myelogenous Leukemia

Kuroda

Yamamoto

Nagoshi

et al. 2010

Molecular Cancer Research

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Tyrosine kinase inhibitors (TKI) against Bcr-Abl are the first-line therapeutics for chronic myelogenous leukemia (CML). However, the resistance to Bcr-Abl TKIs is induced in leukemic cells not only by loss of sensitivity to TKIs through Bcr-Abl-related molecular mechanisms but also by loss of addiction to Bcr-Abl TK activity by acquiring Bcr-Abl-unrelated additional oncogenic mutations. Therefore, the identification of an additional therapeutic target has been anticipated for achievement of a complete cure and to overcome resistance to treatment. We here showed that modified human Galectin-9 (hGal9), a lectin that show specific affinity for β-galactosides, inhibits the proliferation of five CML-derived cell lines by inducing apoptosis at their IC 50 s from 17.5 to 164.9 nmol/L. Our study revealed that activating transcription factor 3 (ATF3), a member of the ATF/ cAMP-responsive element binding protein family transcription factors, is the critical mediator for cell killing by hGal9, and that Noxa is one of the downstream effector molecules of ATF3. Bim, on the other hand, the BH3-only protein essential for apoptosis by Bcr-Abl TKIs, was not associated with hGal9-induced cell death. ATF3-mediated cell death by hGal9 was not hampered by the absence of p53, the presence of mutant Abl T315I , or by P-glycoprotein overexpression. In addition, hGal9 showed the additive growth-inhibitory effect with imatinib on CML cell lines.

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Section: Methodsmentioning

confidence: 99%

Targeting Activating Transcription Factor 3 by Galectin-9 Induces Apoptosis and Overcomes Various Types of Treatment Resistance in Chronic Myelogenous Leukemia

Kuroda

Yamamoto

Nagoshi

et al. 2010

Molecular Cancer Research

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“…The human leukemic cell lines K562, KT-1, BV173 and MYL were all derived from CML-BC patients. 40 Ba/F3/bcr-abl/wt, which expresses wild-type Bcr-Abl, was generated from the murine hematopoietic cell line Ba/F3 as previously described.…”

Section: Methodsmentioning

confidence: 99%

The Bcr-Abl kinase inhibitor INNO-406 induces autophagy and different modes of cell death execution in Bcr-Abl-positive leukemias

et al. 2008

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Bcr-Abl tyrosine kinase (TK) inhibitors are promising therapeutic agents for Bcr-Abl-positive (Bcr-Abl þ ) leukemias. Although they are known to promote caspase-mediated apoptosis, it remains unclear whether caspase-independent cell death-inducing mechanisms are also triggered. Here we demonstrated that INNO-406, a second-generation Bcr-Abl TK inhibitor, induces programmed cell death (PCD) in chronic myelogenous leukemia (CML) cell lines through both caspase-mediated and caspaseindependent pathways. The latter pathways include caspase-independent apoptosis (CIA) and necrosis-like cell death (CIND), and the cell lines varied regarding which mechanism was elicited upon INNO-406 treatment. We also observed that the propensity toward CIA or CIND in cells was strongly associated with cellular dependency on apoptosome-mediated caspase activity. Cells that undergo CIND have a high apoptosome activity potential whereas cells that undergo CIA tend to have a lower potential. Moreover, we found that INNO-406 promotes autophagy. When autophagy was inhibited with chloroquine or gene knockdown of beclin1 by shRNA, INNO-406-induced cell death was enhanced, which indicates that the autophagic response of the tumor cells is protective. These findings suggest new insights into the biology and therapy of Bcr-Abl þ leukemias.

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“…[21][22][23]39 MYL and its imatinib-resistant subclone MYL-R were kind gifts from Dr. Hideo Tanaka (Hiroshima University, Japan). 28 We generated Ba/F3-derived murine hematopoietic cell lines transformed with wt p210-Bcr-Abl (Ba/F3/wt . ) or BcrAbl bearing the E255K (Ba/F3/E255K), T315I (Ba/F3/T315I) or the H396P mutation (Ba/F3/H396P).…”

Section: Methodsmentioning

confidence: 99%

“…28 When compared with MYL, MYL-R was resistant to cell death either by INNO-406 or ABT-737, and the cell death by INNO-406 was increased only when the higher concentration of ABT-737 was combined ( Supplementary Figure 3b, c).…”

Section: Combination Effect Of Inno-406 and Abt-737 On Imatinib-resismentioning

confidence: 97%

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

et al. 2007

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Bcr-Abl is the cause of Philadelphia-positive (Ph þ ) leukemias and also constitutes their principal therapeutic target, as exemplified by dramatic effects of imatinib mesylate. However, mono-targeting of Bcr-Abl does not always achieve complete leukemia eradication, and additional strategies those enable complete elimination of leukemic cells are desired to develop. Here we demonstrate that INNO-406, a much more active Bcr-Abl tyrosine kinase inhibitor than imatinib, augments the activities of several proapoptotic Bcl-2 homology (BH)3-only proteins (Bim, Bad, Bmf and Bik) and induces apoptosis in Ph þ leukemia cells via Bcl-2 family-regulated intrinsic apoptosis pathway. ABT-737, an inhibitor of antiapoptotic Bcl-2 and Bcl-X L , greatly enhanced the apoptosis by INNO-406, even in INNO-406-less sensitive cells with Bcr-Abl point mutations except T315I mutation. In contrast, co-treatment with INNO-406 and other pharmacologic inducers of those BH3-only proteins, such as 17-allylaminogeldanamycin, an heat shock protein-90 inhibitor, or PS-341, a proteasome inhibitor, did not further increase the BH3-only protein levels or sensitize leukemic cells to INNO-406-induced apoptosis, suggesting a limit to how much expression levels of BH3-only proteins can be increased by anticancer agents. Thus, double-barrelled molecular targeting for Bcr-Abl-driven oncogenic signaling and the cell protection by antiapoptotic Bcl-2 family proteins may be the rational therapeutic approach for eradicating Ph þ leukemic cells.

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Establishment and characterization of a novel imatinib‐sensitive chronic myeloid leukemia cell line MYL, and an imatinib‐resistant subline MYL‐R showing overexpression of Lyn

Cited by 37 publications

References 45 publications

Targeting Activating Transcription Factor 3 by Galectin-9 Induces Apoptosis and Overcomes Various Types of Treatment Resistance in Chronic Myelogenous Leukemia

Targeting Activating Transcription Factor 3 by Galectin-9 Induces Apoptosis and Overcomes Various Types of Treatment Resistance in Chronic Myelogenous Leukemia

The Bcr-Abl kinase inhibitor INNO-406 induces autophagy and different modes of cell death execution in Bcr-Abl-positive leukemias

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

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