Spectrum and functional validation of PSMB5 mutations in multiple myeloma

Leukemia
Santiago BarrioK Martin Kortüm

Abstract

Despite an increasing number of approved therapies, multiple myeloma (MM) remains an incurable disease and only a small number of patients achieve prolonged disease control. Some genes have been linked with response to commonly used anti-MM compounds, including immunomodulators (IMiDs) and proteasome inhibitors (PIs). In this manuscript, we demonstrate an increased incidence of acquired proteasomal subunit mutations in relapsed MM compared to newly diagnosed disease, underpinning a potential role of point mutations in the clonal evolution of MM. Furthermore, we are first to present and functionally characterize four somatic PSMB5 mutations from primary MM cells identified in a patient under prolonged proteasome inhibition, with three of them affecting the PI-binding pocket S1. We confirm resistance induction through missense mutations not only to Bortezomib, but also, in variable extent, to the next-generation PIs Carfilzomib and Ixazomib. In addition, a negative impact on the proteasome activity is assessed, providing a potential explanation for later therapy-induced eradication of the affected tumor subclones in this patient.

References

Jul 21, 2004·Journal of Computational Chemistry·Eric F PettersenThomas E Ferrin
Jan 5, 2012·PloS One·Erika SuzukiChristopher J Kirk
Apr 14, 2012·Blood·Jonathan J KeatsP Leif Bergsagel
Jan 17, 2014·Nature Communications·Niccolo BolliNikhil C Munshi
Jan 21, 2015·Structure·Wayne HarshbargerJames Sacchettini
Feb 11, 2015·Nature Genetics·Andrea SottorivaChristina Curtis
Aug 19, 2015·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Brian A WalkerGareth J Morgan
Dec 23, 2016·Leukemia·R FonsecaP Richardson
Dec 29, 2016·Proceedings of the National Academy of Sciences of the United States of America·Peter TsvetkovSusan Lindquist

❮ Previous
Next ❯

Citations

Dec 27, 2019·American Journal of Physiology. Cell Physiology·Paula Saavedra-GarcíaHolger W Auner
Jul 23, 2020·Nature Chemical Biology·Rudolf Pisa, Tarun M Kapoor
Nov 23, 2019·Proceedings of the National Academy of Sciences of the United States of America·Sourav BanerjeeXiaoguang Lei
Sep 14, 2020·Asia-Pacific Journal of Clinical Oncology·Yang Bai, Xing Su
Mar 16, 2019·International Journal of Molecular Sciences·Leo RascheNiels Weinhold
Jul 22, 2019·Journal of Clinical Medicine·Antonio Giovanni SolimandoHermann Einsele
Jun 6, 2020·The Journal of Pathology·Silvia Sevilla-MovillaJoaquin Teixidó
Aug 29, 2019·Frontiers in Oncology·Alexey V Morozov, Vadim L Karpov
Oct 2, 2019·World Journal of Clinical Oncology·Jianbiao Zhou, Wee-Joo Chng
Mar 18, 2020·Frontiers in Oncology·Niccolo BolliCarolina Terragna
Aug 5, 2020·Expert Opinion on Investigational Drugs·Patrick RothMichael Weller
Jun 21, 2020·Molecular Cancer Research : MCR·Chang-Xin ShiA Keith Stewart
Dec 4, 2020·British Journal of Cancer·Takuma Hayashi, Ikuo Konishi
Feb 13, 2021·International Journal of Molecular Sciences·Sang Wu LeeSo Hee Kwon
Jan 8, 2021·Hematology Reports·Niccolò BolliClaudio Cerchione
Jun 22, 2021·ACS Pharmacology & Translational Science·Rachel L Mynott, Craig T Wallington-Beddoe
Oct 31, 2018·Journal of Medicinal Chemistry·Stanley C XieLeann Tilley

❮ Previous
Next ❯

Methods Mentioned

BETA
biopsy
flow cytometry
biopsies
transfection

Software Mentioned

BWA ( Burrows Wheeler Alignment Tool )
Ion Reporter
Chimera
HaplotypeCaller Genome Analysis Toolkit
CASAVA (
SeattleSeq Annotation
configureBclToFastq
Integrative Genomics Viewer ( IGV )

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.