Phosphorylation alters Bim‐mediated Mcl‐1 stabilization and priming

Conage‐Pough, Jason E.; Boise, Lawrence H.

doi:10.1111/febs.14505

Cited by 18 publications

(15 citation statements)

References 78 publications

(104 reference statements)

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“…Mcl-1 also increased upon venetoclax or S-63845 treatment in vitro (Figure 3C), and we propose that Mcl-1 is not upregulated but rather stabilized upon interaction with Bim or S-63845, which are previously reported effects [23][24][25]31 . Increase of Bcl-2 or Bcl-XL are most likely not due to stabilization since they have a much longer half-life than Mcl-1 and Bfl-1 32 .…”

Section: Discussionsupporting

confidence: 80%

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Changes in Bcl-2 members after ibrutinib or venetoclax uncover functional hierarchy in determining resistance to venetoclax in CLL

Haselager

Kielbassa

Burg

et al. 2020

Blood

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Chronic lymphocytic leukemia (CLL) cells cycle between lymph node (LN) and peripheral blood (PB) and display major shifts in Bcl-2 family members between those compartments. Specifically, Bcl-XL and Mcl-1, which are not targeted by the Bcl-2 inhibitor venetoclax, are increased in the LN. Since ibrutinib forces CLL cells out of the LN, we hypothesized that ibrutinib may thereby affect expression of Bcl-XL and Mcl-1 and sensitize CLL cells to venetoclax. We investigated expression of Bcl-2 family members in patients under ibrutinib or venetoclax treatment combined with dissecting functional interactions of Bcl-2 family members in an in vitro model for venetoclax resistance. In the PB, recent LN emigrants had higher Bcl-XL and Mcl-1 expression than cells immigrating back to the LN. Under ibrutinib treatment, this distinction collapsed, and significantly, the pre-treatment profile reappeared in patients who relapsed on ibrutinib. In response to venetoclax however, Bcl-2 members displayed an early increase, underlining the different modes of action of these two drugs. Profiling by BH3 mimetics was performed in CLL cells fully resistant to venetoclax due to CD40-mediated induction of Bcl-XL, Mcl-1 and Bfl-1. Several dual or triple combinations of BH3 mimetics were highly synergistic in restoring killing of CLL cells. Lastly, we demonstrated that pro-apoptotic Bim interacts with anti-apoptotic Bcl-2 members in a sequential manner: Bcl-2>Bcl-XL>Mcl-1>Bfl-1. Combined, the data indicate that Bcl-XL is more important in venetoclax resistance than Mcl-1 and provide biological rationale for potential synergy between ibrutinib and venetoclax.

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Section: Discussionsupporting

confidence: 80%

“…Mcl-1 is unstable and known to be stabilized at the protein level by BH3 protein binding [23][24][25] , suggesting that the observed increase in Mcl-1 after venetoclax treatment may reflect its binding to Bim in vivo. Altogether, these results show that levels of Mcl-1, Bcl-XL and Bcl-2 increase upon venetoclax treatment.…”

Section: Only Formentioning

confidence: 99%

Changes in Bcl-2 members after ibrutinib or venetoclax uncover functional hierarchy in determining resistance to venetoclax in CLL

Haselager

Kielbassa

Burg

et al. 2020

Blood

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“…MCL-1 is a key survival factor for many cell types, allowing it to strictly regulate cell fate. In normal cells, MCL-1 sequesters the BH3-only activators BIM, BID and PUMA or neutralizes the effector proteins BAX and BAK, thereby antagonizing apoptosis [ 32 ] (Fig. 3 a).…”

Section: Introductionmentioning

confidence: 99%

Targeting MCL-1 in cancer: current status and perspectives

et al. 2021

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Myeloid leukemia 1 (MCL-1) is an antiapoptotic protein of the BCL-2 family that prevents apoptosis by binding to the pro-apoptotic BCL-2 proteins. Overexpression of MCL-1 is frequently observed in many tumor types and is closely associated with tumorigenesis, poor prognosis and drug resistance. The central role of MCL-1 in regulating the mitochondrial apoptotic pathway makes it an attractive target for cancer therapy. Significant progress has been made with regard to MCL-1 inhibitors, some of which have entered clinical trials. Here, we discuss the mechanism by which MCL-1 regulates cancer cell apoptosis and review the progress related to MCL-1 small molecule inhibitors and their role in cancer therapy.

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“…IL6 upregulates Mcl-1 in a STAT3 dependent manner and induces phosphorylation of Bim, thus increasing affinity of Bim for Mcl-1 over Bcl-2/Bcl-x. This increased binding of the two proteins ultimately leads to stabilization of Mcl-1 ( 93 , 94 ).…”

Section: The Role Of the Bone Marrow Microenvironmentmentioning

confidence: 99%

Game of Bones: How Myeloma Manipulates Its Microenvironment

et al. 2021

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Multiple myeloma is a clonal disease of long-lived plasma cells and is the second most common hematological cancer behind Non-Hodgkin’s Lymphoma. Malignant transformation of plasma cells imparts the ability to proliferate, causing harmful lesions in patients. In advanced stages myeloma cells become independent of their bone marrow microenvironment and form extramedullary disease. Plasma cells depend on a rich array of signals from neighboring cells within the bone marrow for survival which myeloma cells exploit for growth and proliferation. Recent evidence suggests, however, that both the myeloma cells and the microenvironment have undergone alterations as early as during precursor stages of the disease. There are no current therapies routinely used for treating myeloma in early stages, and while recent therapeutic efforts have improved patients’ median survival, most will eventually relapse. This is due to mutations in myeloma cells that not only allow them to utilize its bone marrow niche but also facilitate autocrine pro-survival signaling loops for further progression. This review will discuss the stages of myeloma cell progression and how myeloma cells progress within and outside of the bone marrow microenvironment.

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Phosphorylation alters Bim‐mediated Mcl‐1 stabilization and priming

Cited by 18 publications

References 78 publications

Changes in Bcl-2 members after ibrutinib or venetoclax uncover functional hierarchy in determining resistance to venetoclax in CLL

Changes in Bcl-2 members after ibrutinib or venetoclax uncover functional hierarchy in determining resistance to venetoclax in CLL

Targeting MCL-1 in cancer: current status and perspectives

Game of Bones: How Myeloma Manipulates Its Microenvironment

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