Hypoxia-induced p38 MAPK activation reduces Mcl-1 expression and facilitates sensitivity towards BH3 mimetics in chronic lymphocytic leukemia

Huelsemann, Malte; Patz, Michaela; Beckmann, Laura; Brinkmann, Kerstin; Otto, Teresa; Fandrey, Joachim; Becker, H.; Theurich, Sebastian; Bergwelt‐Baildon, Michael von; Pallasch, Christian P.; Zahedi, René P.; Kashkar, Hamid; Reinhardt, Hans Christian; Hallek, Michael; Wendtner, Clemens; Frenzel, Lukas P.

doi:10.1038/leu.2014.320

Cited by 28 publications

(32 citation statements)

References 14 publications

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“…8,16 We placed glioma cells lines U87 and U373 under hypoxia for a 72 hour time course and determined the amount of cell death. After 72 hours, the amount of cell death increased from 5% to 36% in U87 cells and from 9% to 28% in U373 cells (Fig.…”

Section: Bcl-2 Family Member Mcl-1 Expression Is Reduced Under Hypoxiamentioning

confidence: 99%

Bcl-2 family member Mcl-1 expression is reduced under hypoxia by the E3 ligase FBW7 contributing to BNIP3 induced cell death in glioma cells

Chen

Henson

Xiao

et al. 2015

Cancer Biology & Therapy

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Section: Bcl-2 Family Member Mcl-1 Expression Is Reduced Under Hypoxiamentioning

confidence: 99%

Bcl-2 family member Mcl-1 expression is reduced under hypoxia by the E3 ligase FBW7 contributing to BNIP3 induced cell death in glioma cells

Chen

Henson

Xiao

et al. 2015

Cancer Biology & Therapy

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“…Hypoxia induces p38 activation, which in turn downregulates MCL-1 expression and increases the sensitivity of CLL toward BH3 mimetics. 72 Treatment with gossypol altered the splicing of MCL-1L to MCL-1s, 27 which was reported to act as a pro-apoptotic protein. Similarly, the SF3B1 inhibitor spliceostatin A (SSA) altered the splicing of MCL-1L to MCL-1s, which was coincident with induction of apoptosis in CLL cells.…”

mentioning

confidence: 99%

Development of venetoclax for therapy of lymphoid malignancies

Zhu

Almasan

2017

DDDT

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B-cell lymphoma-2 (BCL-2) family dysfunction and impairment of apoptosis are common in most B-cell lymphoid malignancies. Venetoclax (Venclexta™, formerly ABT-199, GDC-0199) is a highly selective BCL-2 inhibitor, which mimics its BCL-2 homology 3-domain to induce apoptosis. It was approved for treatment of previously treated chronic lymphocytic leukemia (CLL) patients with 17p deletion early in 2016. It has also been in clinical trials for other B-cell lymphoid malignancies. Unlike the other recently approved targeted agents idelalisib and ibrutinib, so far there has been no relapse reported in some patients. Also, unlike the other targeted agents, it is effective against tumor cells that reside in the blood marrow. Despite its promising outcome in CLL, preclinical data have already uncovered mechanistic insights underlying venetoclax resistance, such as upregulation of MCL-1 or BCL-xL expression and protective signaling from the microenvironment. In this review, we describe the role of the BCL-2 family in the pathogenesis of B-cell lymphoid malignancies, the development of venetoclax, and its current clinical outcome in CLL and other B-cell malignancies. We also discuss the resistance mechanisms that develop following venetoclax therapy, potential strategies to overcome them, and how this knowledge can be translated into clinical applications.

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“…As a result, the canonical MEK/ERK MAPK, the PI3K/AKT and the NFkB pathways become activated to antagonize (DNA damage-induced) apoptosis and to stimulate cell proliferation. For instance, AKT is critical for sustained expression and p38 for suppression of the anti-apoptotic molecule MCL1 in CLL cells [27,28]. Furthermore, NFkB-dependent transactivation of the anti-apoptotic genes Bcl2 , Bcl-xl and Bfl1/A1 , as well as different inhibitor of apoptosis proteins (IAPs) has been shown to occur downstream of BCR and TLR signaling in CLL cells [29,30,31].…”

Section: Cll Cells Receive Critical Survival Signals From Their Micromentioning

confidence: 99%

“…Despite its evident importance in solid tumors, the impact of hypoxia on CLL is only poorly understood [44]. Indeed, it was shown that hypoxia directly impacts on DDR signaling by protecting CLL cells from fludarabine- and bendamustin-triggered apoptosis, which is a reasonable explanation for why CLL cells are not efficiently targeted in the tumor microenvironment and display a niche for relapse [28]. In contrast, the efficacy towards the BH3-mimetic ABT-737 and the clinical compound venetoclax (ABT-199) was increased [28].…”

Section: Hypoxia An Underestimated Factormentioning

confidence: 99%

“…Indeed, it was shown that hypoxia directly impacts on DDR signaling by protecting CLL cells from fludarabine- and bendamustin-triggered apoptosis, which is a reasonable explanation for why CLL cells are not efficiently targeted in the tumor microenvironment and display a niche for relapse [28]. In contrast, the efficacy towards the BH3-mimetic ABT-737 and the clinical compound venetoclax (ABT-199) was increased [28]. This was due to uncoupled activation of central signaling pathways: while phosphorylation of AKT, ERK1/2 and NFkB was reduced, p38 became hyper-phosphorylated under hypoxic conditions [28].…”

Section: Hypoxia An Underestimated Factormentioning

confidence: 99%

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Concepts of Chronic Lymphocytic Leukemia Pathogenesis: DNA Damage Response and Tumor Microenvironment

Frenzel

Reinhardt²,

Pallasch³

2016

Oncol Res Treat

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Pathogenesis of chronic lymphocytic leukemia (CLL) is characterized by specific genetic aberrations and alterations of cellular signaling pathways. In particular, a disturbed DNA damage response (DDR) and an activated B-cell receptor signaling pathway play a major role in promoting CLL cell survival. External stimuli are similarly essential for CLL cell survival and lead to activation of the PI3K/AKT and MAPK pathways. Activation of nuclear factor-kappa B (NFkB) influences the disturbed anti-apoptotic balance of CLL cells. Losses or disabling mutations in TP53 and ATM are frequent events in chemotherapy-naïve patients and are further enriched in chemotherapy-resistant patients. As these lesions define key regulatory elements of the DDR pathway, they also determine treatment response to genotoxic therapy. Novel therapeutic strategies therefore try to circumvent defective DDR signaling and to suppress the pro-survival stimuli received from the tumor microenvironment. With increasing knowledge on specific genetic alterations of CLL, we may be able to target CLL cells more efficiently even in the situation of mutated DDR pathways or protection by microenvironmental stimuli.

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Hypoxia-induced p38 MAPK activation reduces Mcl-1 expression and facilitates sensitivity towards BH3 mimetics in chronic lymphocytic leukemia

Cited by 28 publications

References 14 publications

Bcl-2 family member Mcl-1 expression is reduced under hypoxia by the E3 ligase FBW7 contributing to BNIP3 induced cell death in glioma cells

Bcl-2 family member Mcl-1 expression is reduced under hypoxia by the E3 ligase FBW7 contributing to BNIP3 induced cell death in glioma cells

Development of venetoclax for therapy of lymphoid malignancies

Concepts of Chronic Lymphocytic Leukemia Pathogenesis: DNA Damage Response and Tumor Microenvironment

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