Identification of MCL1 as a novel target in neoplastic mast cells in systemic mastocytosis: inhibition of mast cell survival by MCL1 antisense oligonucleotides and synergism with PKC412

Aichberger, Karl J.; Mayerhofer, Matthias; Gleixner, Karoline V.; Krauth, Maria‐Theresa; Gruze, Alexander; Pickl, Winfried F.; Wacheck, Volker; Selzer, Edgar; Müllauer, Leonhard; Agis, Hermine; Sillaber, Christian; Valent, Peter

doi:10.1182/blood-2006-07-032714

Cited by 64 publications

(62 citation statements)

References 66 publications

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“…4A). Our findings were consistent with the report that silencing Mcl-1 by oligonucleotides resulted in reduced survival and increased apoptosis, and showed synergism with PKC412 in HMC-1.2 cells (33). Therefore, these results indicated that Mcl-1 played a significant role in ponatinib-induced apoptosis in HMC-1.2 cells.…”

Section: Mcl-1 Plays a Significant Role In Ponatinib-induced Apoptosissupporting

confidence: 82%

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Ponatinib Induces Apoptosis in Imatinib-Resistant Human Mast Cells by Dephosphorylating Mutant D816V KIT and Silencing β-Catenin Signaling

Jin

Ding

Pan

2014

Molecular Cancer Therapeutics

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Gain-of-function mutations of membrane receptor tyrosine kinase KIT, especially gatekeeper D816V point mutation in KIT, render kinase autoactivation, disease progression, and poor prognosis. D816V KIT is found in approximately 80% of the patients with systemic mastocytosis, and is resistant to the first and second generations of tyrosine kinase inhibitors (TKI). The purpose of this investigation was aimed at exploring whether ponatinib (AP24534), a novel effective TKI against T315I Bcr-Abl, was active against D816V KIT. We discovered that ponatinib abrogated the phosphorylation of KIT harboring either V560G (sensitive to imatinib) or D816V mutation (resistant to imatinib) and the downstream signaling transduction. Ponatinib inhibited the growth of D816V KIT-expressing cells in culture and nude mouse xenografted tumor. Ponatinib triggered apoptosis by inducing the release of cytochrome c and AIF, downregulation of Mcl-1. Furthermore, ponatinib abrogated the phosphorylation of b-catenin at the site Y654, suppressed the translocation of b-catenin, and inhibited the transcription and DNA binding of TCF and the expression of its targets (e.g., AXIN2, c-MYC, and CCND1). Moreover, ponatinib was highly active against xenografted D816V KIT tumors in nude mice and significantly prolonged the survival of mice with aggressive systemic mastocytosis or mast cell leukemia by impeding the expansion and infiltration of mast cells with imatinibresistant D814Y KIT. Our findings warrant a clinical trial of ponatinib in patients with systemic mastocytosis harboring D816V KIT. Mol Cancer Ther; 13(5); 1217-30. Ó2014 AACR.

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Section: Mcl-1 Plays a Significant Role In Ponatinib-induced Apoptosissupporting

confidence: 82%

“…These results were in accord with the previous reports with TKIs (e.g., PKC412, AMN107, and imatinib; ref. 33) and agents such as triptolide (43) and homoharingtonine (25) in human mast cells. Our results suggest that Mcl-1 was reduced in a ubiquitin proteasome pathway-independent and caspase-3-independent manner in response to ponatinib.…”

Section: Discussionmentioning

confidence: 99%

Ponatinib Induces Apoptosis in Imatinib-Resistant Human Mast Cells by Dephosphorylating Mutant D816V KIT and Silencing β-Catenin Signaling

Jin

Ding

Pan

2014

Molecular Cancer Therapeutics

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“…S1). This phenomenon is also observed in response to PKC412, dasatinib, and other conventional therapeutic agents (1). This may partly be explained by the more downregulation of Mcl-1 (Fig.…”

Section: Discussionmentioning

confidence: 73%

“…Overexpression of Mcl-1 protects tumor cells from apoptosis induced by diverse agents, including flavopiridol, triptolide, and sorafenib (25,27,43). Mcl-1 is overexpressed in neoplastic cells in hematologic malignancies, including CML and SM (1,44). Targeting Mcl-1 by antisense oligonucleotide or siRNA has been shown to induce apoptosis in mast cells and increase sensitivity to tyrosine kinase inhibitors (e.g., PKC412, AMN107, and imatinib; ref.…”

Section: Discussionmentioning

confidence: 99%

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The Antitumor Activity of Homoharringtonine against Human Mast Cells Harboring the KIT D816V Mutation

Jin

Lu²,

Cao³

et al. 2010

Molecular Cancer Therapeutics

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Gain-of-function mutations of the receptor tyrosine kinase KIT play a critical role in the pathogenesis of systemic mastocytosis (SM) and gastrointestinal stromal tumors. The various juxtamembrane type of KIT mutations, including V560G, are found in 60% to 70% of patients with gastrointestinal stromal tumors; loop mutant D816V, which exists in ∼80% of SM patients, is completely resistant to imatinib. In the present study, we hypothesized that homoharringtonine (HHT), a protein synthesis inhibitor, would decrease the level of KIT protein by inhibiting translation, resulting in a decreased level of phospho-KIT and abrogating its constitutive downstream signaling. Imatinib-sensitive HMC-1.1 cells harboring the mutation V560G in the juxtamembrane domain of KIT, imatinib-resistant HMC-1.2 cells harboring both V560G and D816V mutations, and murine P815 cells were treated with HHT and analyzed in terms of growth, apoptosis, and signal transduction. The in vivo antitumor activity was evaluated by using the murine mast cell leukemia model. Our results indicated that HHT effectively inhibited the growth and induced apoptosis in cells bearing both V560G and D816V or D814Y KIT. Additionally, HHT inhibited the KIT-dependent phosphorylation of downstream signaling molecules Akt, signal transducer and activator of transcription 3 and 5, and extracellular signal-regulated kinase 1/2. Furthermore, HHT significantly prolonged the survival duration of mice with aggressive SM or mast cell leukemia by inhibiting the expansion and infiltration of imatinib-resistant mast tumor cells harboring imatinib-resistant D814Y KIT. Collectively, we show that HHT circumvents D816V KITelicited imatinib resistance. Our findings warrant a clinical trial of HHT in patients with SM harboring D816V or D814Y KIT. Mol Cancer Ther; 9(1); 211-23. ©2010 AACR.

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Mast Cell Apoptosis and Survival

Ekoff

Nilsson

2011

Mast Cell Biology

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Mast cells are enigmatic cells that are recognized as critical components of our immune system. They are strategically localized at the host/environment interface, display a long lifespan once situated in tissues and have the ability to produce, store and upon activation, release immuno-regulatory molecules. In specific acute and chronic conditions, mast cell accumulation, activation and release of mediators are important for the initiation and perpetuation of the inflammation associated with these disease states. During the past decade, regulatory pathways for mast cell survival have been elucidated, which have, in part, helped to explain the increased number and survival of mast cells observed during inflammatory reactions associated with, e.g., the allergic response. One key group of regulators involved in cell survival and apoptosis is the Bcl-2 family of proteins. The Bcl-2 family consists of pro- and anti-apoptotic members, where the balance between these members determines cellular fate via protein-protein interactions. In this chapter, we will discuss the regulation of mast cell apoptosis and survival and how understanding the mechanisms by which Bcl-2 family members regulate mast cell survival could lead to the identification of key proteins that affect the severity of inflammation. This knowledge could be used to develop treatments for mast cell disorders such as mastocytosis and other inflammatory diseases where mast cells are involved.

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Identification of MCL1 as a novel target in neoplastic mast cells in systemic mastocytosis: inhibition of mast cell survival by MCL1 antisense oligonucleotides and synergism with PKC412

Abstract: MCL-1 is a Bcl-2 family member that has been described as antiapoptotic in various myeloid neoplasms. Therefore, MCL-1 has been suggested as a potential new therapeutic target.

Cited by 64 publications

References 66 publications

Ponatinib Induces Apoptosis in Imatinib-Resistant Human Mast Cells by Dephosphorylating Mutant D816V KIT and Silencing β-Catenin Signaling

Ponatinib Induces Apoptosis in Imatinib-Resistant Human Mast Cells by Dephosphorylating Mutant D816V KIT and Silencing β-Catenin Signaling

The Antitumor Activity of Homoharringtonine against Human Mast Cells Harboring the KIT D816V Mutation

Mast Cell Apoptosis and Survival

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