Title : Binding of Released Bim to Mcl-1 is a Mechanism of Intrinsic Resistance to ABT-199 which can be Overcome by Combination with Daunorubicin or Cytarabine in AML Cells.

Pub. Date : 2016 Sep 1

PMID : 27103402






10 Functional Relationships(s)
Download
Sentence
Compound Name
Protein Name
Organism
1 Binding of Released Bim to Mcl-1 is a Mechanism of Intrinsic Resistance to ABT-199 which can be Overcome by Combination with Daunorubicin or Cytarabine in AML Cells. 2,2'-azino-di-(3-ethylbenzothiazoline)-6-sulfonic acid MCL1 apoptosis regulator, BCL2 family member Homo sapiens
2 EXPERIMENTAL DESIGN: Western blots and real-time RT-PCR were used to determine levels of Mcl-1 after ABT-199 treatment alone or in combination with cytarabine or daunorubicin. 2,2'-azino-di-(3-ethylbenzothiazoline)-6-sulfonic acid MCL1 apoptosis regulator, BCL2 family member Homo sapiens
3 Lentiviral short hairpin RNA knockdown of Bim and CRISPR knockdown of Mcl-1 were used to confirm their role in resistance to ABT-199. 2,2'-azino-di-(3-ethylbenzothiazoline)-6-sulfonic acid MCL1 apoptosis regulator, BCL2 family member Homo sapiens
4 ABT-199 treatment resulted in increased levels of Mcl-1 protein, unchanged or decreased Mcl-1 transcript levels, and increased Mcl-1 protein half-life, suggesting that the association with Bim plays a role in stabilizing Mcl-1 protein. 2,2'-azino-di-(3-ethylbenzothiazoline)-6-sulfonic acid MCL1 apoptosis regulator, BCL2 family member Homo sapiens
5 ABT-199 treatment resulted in increased levels of Mcl-1 protein, unchanged or decreased Mcl-1 transcript levels, and increased Mcl-1 protein half-life, suggesting that the association with Bim plays a role in stabilizing Mcl-1 protein. 2,2'-azino-di-(3-ethylbenzothiazoline)-6-sulfonic acid MCL1 apoptosis regulator, BCL2 family member Homo sapiens
6 ABT-199 treatment resulted in increased levels of Mcl-1 protein, unchanged or decreased Mcl-1 transcript levels, and increased Mcl-1 protein half-life, suggesting that the association with Bim plays a role in stabilizing Mcl-1 protein. 2,2'-azino-di-(3-ethylbenzothiazoline)-6-sulfonic acid MCL1 apoptosis regulator, BCL2 family member Homo sapiens
7 ABT-199 treatment resulted in increased levels of Mcl-1 protein, unchanged or decreased Mcl-1 transcript levels, and increased Mcl-1 protein half-life, suggesting that the association with Bim plays a role in stabilizing Mcl-1 protein. 2,2'-azino-di-(3-ethylbenzothiazoline)-6-sulfonic acid MCL1 apoptosis regulator, BCL2 family member Homo sapiens
8 Combining conventional chemotherapeutic agent cytarabine or daunorubicin with ABT-199 resulted in increased DNA damage along with decreased Mcl-1 protein levels, compared with ABT-199 alone, and synergistic induction of cell death in both AML cell lines and primary patient samples obtained from AML patients at diagnosis. 2,2'-azino-di-(3-ethylbenzothiazoline)-6-sulfonic acid MCL1 apoptosis regulator, BCL2 family member Homo sapiens
9 CONCLUSIONS: Our results demonstrate that sequestration of Bim by Mcl-1 is a mechanism of intrinsic ABT-199 resistance and supports the clinical development of ABT-199 in combination with cytarabine or daunorubicin for the treatment of AML. 2,2'-azino-di-(3-ethylbenzothiazoline)-6-sulfonic acid MCL1 apoptosis regulator, BCL2 family member Homo sapiens
10 CONCLUSIONS: Our results demonstrate that sequestration of Bim by Mcl-1 is a mechanism of intrinsic ABT-199 resistance and supports the clinical development of ABT-199 in combination with cytarabine or daunorubicin for the treatment of AML. 2,2'-azino-di-(3-ethylbenzothiazoline)-6-sulfonic acid MCL1 apoptosis regulator, BCL2 family member Homo sapiens