Pharmacologic inhibition of the ubiquitin-activating enzyme induces ER stress and apoptosis in chronic lymphocytic leukemia and ibrutinib-resistant mantle cell lymphoma cells

Scott Best, Tingting Liu, Nur Bruss, Adam Kittai, Allison Berger, Alexey Danilov

Research output: Contribution to journalArticle

Abstract

With the advent of proteasome inhibitors (bortezomib) and pleiotropic pathway modulators which target cereblon E3 ligase (lenalidomide), the ubiquitin-proteasome system has emerged as a tractable target in non-Hodgkin lymphoma and multiple myeloma. Here we report that TAK-243, a small molecule inhibitor of the ubiquitin-activating enzyme (UAE), induced ER stress and the unfolded protein response in primary chronic lymphocytic leukemia cells, facilitating cell death. Moreover, targeting UAE was effective in ibrutinib-resistant mantle cell lymphoma cell lines and primary cells in vitro. Thus, UAE is a promising target in lymphoid malignancies, including ibrutinib-resistant lymphomas, an area of unmet medical need.

Original languageEnglish (US)
JournalLeukemia and Lymphoma
DOIs
StatePublished - Jan 1 2019

Fingerprint

Ubiquitin-Activating Enzymes
Mantle-Cell Lymphoma
B-Cell Chronic Lymphocytic Leukemia
Apoptosis
Unfolded Protein Response
Proteasome Inhibitors
Ubiquitin-Protein Ligases
Proteasome Endopeptidase Complex
Heat-Shock Proteins
Multiple Myeloma
Non-Hodgkin's Lymphoma
Lymphoma
Cell Death
Cell Line
PCI 32765
Neoplasms

Keywords

  • CLL
  • TAK-243
  • Ubiquitin-activating enzyme

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Pharmacologic inhibition of the ubiquitin-activating enzyme induces ER stress and apoptosis in chronic lymphocytic leukemia and ibrutinib-resistant mantle cell lymphoma cells. / Best, Scott; Liu, Tingting; Bruss, Nur; Kittai, Adam; Berger, Allison; Danilov, Alexey.

In: Leukemia and Lymphoma, 01.01.2019.

Research output: Contribution to journalArticle

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