Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia

Konopleva, Marina; Contractor, Rooha; Tsao, Twee; Samudio, Ismael; Ruvolo, Peter P.; Kitada, Shinichi; Deng, Xingming; Zhai, Dayong; Shi, Yue; Sneed, Troy; Verhaegen, Monique; Soengas, Marı́a S.; Ruvolo, Vivian; McQueen, Teresa; Schober, Wendy; Watt, Julie C.; Jiffar, Tilahun; Ling, Xiaoyang; Marini, Frank C.; Harris, David; Dietrich, Martin; Estrov, Zeev; McCubrey, James A.; May, W. Stratford; Reed, John C.; Andreeff, Michael

doi:10.1016/j.ccr.2006.10.006

Cited by 933 publications

(987 citation statements)

References 57 publications

Supporting

Mentioning

933

Contrasting

Order By: Relevance

“…24 Mcl-1 expression has been found to be associated with resistance of cells to ABT-737. 25,26 Our results show that the Ku70-deficient MEF cells are more sensitive to ABT-737 than WT MEF cells (Figure 1c, right panel), indicating that downregulation of Mcl-1 by disruption of Ku70 can sensitize cells to Bcl2 inhibition.…”

Section: Resultsmentioning

confidence: 79%

Role of Ku70 in deubiquitination of Mcl-1 and suppression of apoptosis

Wang

Xie

et al. 2014

Cell Death Differ

View full text Add to dashboard Cite

Mcl-1 is a unique antiapoptotic Bcl2 family member with a short half-life due to its rapid turnover through ubiquitination. We discovered that Ku70, a DNA double-strand break repair protein, functions as a deubiquitinase to stabilize Mcl-1. Ku70 knockout in mouse embryonic fibroblast (MEF) Mcl-1 is an antiapoptotic molecule that is overexpressed in various types of cancers, including lung cancer, 1 leukemia, 2 lymphoma, 3 hepatocellular carcinoma 4 and so on. In addition to its antiapoptotic function, Mcl-1 is also an oncoprotein that promotes the development of cancer. 5 In contrast to other Bcl2 family members such as Bcl2 and Bcl-XL, Mcl-1 is unique in its short half-life (30 min-3 h) and short-term prosurvival function, which probably relates to the presence of a long proline-, glutamic acid-, serine-and threonine-rich (PEST) region upstream of the Bcl2 homology (BH) domain. 1 The mechanism(s) that stabilizes the Mcl-1 protein are critical for its long-term survival function. Mcl-1 protein can be phosphorylated at multiple sites that distinctly regulate Mcl-1 protein turnover. For example, extracellular signal-regulated kinase 1/2-mediated T163 site phosphorylation enhances the half-life and antiapoptotic function of Mcl-1. 1,6 In contrast, S159 phosphorylation by GSK-3b facilitates Mcl-1 ubiquitination and degradation to reduce its survival activity. 7 Ubiquitination and deubiquitination are two reversible processes that can control protein stability. E3 ligases and deubiquitinases (deubiquitinating enzymes (DUBs)) are two groups of regulatory enzymes that orchestrate the ubiquitination levels of target proteins in eukaryotic cells. 8 Recently, Mule and FBW7 have been identified as Mcl-1 ubiquitin E3 ligases that can directly induce polyubiquitination and degradation of Mcl-1. 9,10 Inversely, USP9X has been demonstrated as the Mcl-1 deubiquitinase that removes the Lys 48-linked polyubiquitin chains that normally mark Mcl-1 for proteasomal degradation, leading to stabilization of Mcl-1. 3 Therefore, the stability of Mcl-1 in cells is tightly regulated by its E3 ligases and deubiquitinase, which is dependent on Mcl-1 phosphorylation status. 3,11 Ku70 is a protein that binds to DNA double-strand break (DSB) ends and is required for the non-homologous endjoining pathway of DSB repair. 12-15 The Ku70 protein consists of three structural domains, including the N-terminal, central (that is, DNA binding) and C-terminal domains. 16,17 Ku70 usually heterodimerizes with Ku86, which forms a functional complex for DSB repair. By forming a bridge between the broken DNA ends, the Ku70/Ku86 heterodimer acts to structurally support and align the DNA ends, to protect them from degradation and to prevent promiscuous binding to unbroken DNA. Ku70/Ku86 effectively aligns the DNA, while still allowing access of polymerases, nucleases and ligases to the broken DNA ends to promote end joining. 18 In some cases, a fourth domain is present at the C terminus of Ku86, which binds to the DNA-dependent protein kinase catalytic subunit...

show abstract

Section: Resultsmentioning

confidence: 79%

Role of Ku70 in deubiquitination of Mcl-1 and suppression of apoptosis

Wang

Xie

et al. 2014

Cell Death Differ

View full text Add to dashboard Cite

show abstract

“…Thus, the effects of Gfi-1 could be mimicked by inhibition of STAT 5 and Mcl-1 expression and/or activity. Pharmacological inhibition of Mcl-1 and STAT 5 activity suppresses proliferation and colony formation of p210BCR/ABL expressing cells In contrast to ABT-737 which antagonizes Bcl-2 and BCL-XL, 30,31 Obatoclax is a pan-Bcl-2 inhibitor which also blocks the activity of Mcl-1. 32,33 Thus, we treated K562 cells with Obatoclax (500 nM) and assessed their proliferation and colony formation.…”

Section: Resultsmentioning

confidence: 99%

Gfi-1 inhibits proliferation and colony formation of p210BCR/ABL-expressing cells via transcriptional repression of STAT 5 and Mcl-1

et al. 2012

View full text Add to dashboard Cite

Expression of the transcription repressor Gfi-1 is required for the maintenance of murine hematopoietic stem cells. In human cells, ectopic expression of Gfi-1 inhibits and RNA interference-mediated Gfi-1 downregulation enhances proliferation and colony formation of p210BCR/ABL expressing cells. To investigate the molecular mechanisms that may explain the effects of perturbing Gfi-1 expression in human cells, Gfi-1-regulated genes were identified by microarray analysis in K562 cells expressing the tamoxifen-regulated Gfi-1-ER protein.STAT 5B and Mcl-1, two genes important for the proliferation and survival of hematopoietic stem cells, were identified as direct and functionally relevant Gfi-1 targets in p210BCR/ABL-transformed cells because: (i) their expression and promoter activity was repressed by Gfi-1 and (ii) when constitutively expressed blocked the proliferation and colony formation inhibitory effects of Gfi-1. Consistent with these findings, genetic or pharmacological inhibition of STAT 5 and/or Mcl-1 markedly suppressed proliferation and colony formation of K562 and CD34 þ chronic myelogenous leukemia (CML) cells. Together, these studies suggest that the Gfi-1STAT 5B/Mcl-1 regulatory pathway identified here can be modulated to suppress the proliferation and survival of p210BCR/ABL-transformed cells including CD34 þ CML cells.

show abstract

“…The drugs tested included 17-allylaminogeldanamycin (17-AAG), a heat shock protein (HSP)-90 inhibitor and PS-341, a proteasome inhibitor; both have previously been shown to elevate Bim, Bad, Bmf or Bik expression. [15][16][17][18] We also examined whether the killing of INNO-406 could be enhanced by co-treatment with ABT-737, a drug that decreases the antiapoptotic barrier imposed by the antiapoptotic Bcl-2 family members Bcl-2, Bcl-X L and Bcl-w. 19,20 Our study shows that simultaneously targeting both pro-and antiapoptotic molecules augments the killing achieved with INNO-406, even in Bcr-Abl þ leukemias bearing imatinib-resistant Bcr-Abl point mutations. Notably, like Ph þ leukemias, most cancers maintain and propagate themselves by resisting apoptosis and enhancing cell proliferation.…”

mentioning

confidence: 79%

“…Although the mechanism has not been fully elucidated, Mcl-1 might have important role in the combination of INNO-406 and ABT-737. 19,34 This combination effect could be explained by the neutralization of Mcl-1 by Bim, which was not only induced by INNO-406 but also dissociated from Bim/Bcl-2 complex by ABT-737. 19,34 Indeed, the combination effect was largely abrogated in Mcl-1 highly expressing MYL-R (Supplementary Figure 3a, c).…”

Section: Discussionmentioning

confidence: 99%

“…19,34 This combination effect could be explained by the neutralization of Mcl-1 by Bim, which was not only induced by INNO-406 but also dissociated from Bim/Bcl-2 complex by ABT-737. 19,34 Indeed, the combination effect was largely abrogated in Mcl-1 highly expressing MYL-R (Supplementary Figure 3a, c). Collectively, these results suggest the involvement of Mcl-1 in determining the sensitivity for the combination therapy of INNO-406 and ABT-737.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

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.

show abstract

Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia

Cited by 933 publications

References 57 publications

Role of Ku70 in deubiquitination of Mcl-1 and suppression of apoptosis

Role of Ku70 in deubiquitination of Mcl-1 and suppression of apoptosis

Gfi-1 inhibits proliferation and colony formation of p210BCR/ABL-expressing cells via transcriptional repression of STAT 5 and Mcl-1

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

Contact Info

Product

Resources

About