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Functional role and therapeutic targeting of p21-associated kinase 4 (PAK4) in Multiple Myeloma

ABSTRACT: Dysregulated oncogenic serine/threonine kinases play a pathological role in diverse forms of malignancies, including multiple myeloma (MM), and thus represent potential therapeutic targets. Here, we evaluated the biological and functional role of p21-activated kinase 4 (PAK4), and its potential as a new target in MM for clinical applications. PAK4 promoted MM cell growth and survival via activation of MM survival signaling pathways, including the MEK-ERK pathway. Furthermore, treatment with orally bioavailable PAK4 allosteric modulator (KPT-9274) significantly impacted MM cell growth and survival in a large panel of MM cell lines and primary MM cells alone and in the presence of bone marrow microenvironment. Intriguingly, we have identified FGFR3 as a novel binding partner of PAK4 and observed significant activity of KPT-9274 against t(4;14)-positive MM cells. These data support PAK4 as an oncogene in myeloma, and provide the rationale for the clinical evaluation of PAK4 modulator in myeloma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE93745 | GEO | 2017/01/19

SECONDARY ACCESSION(S): PRJNA362287

REPOSITORIES: GEO

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2017-05-01 | GSE86871 | GEO

Dual-inhibition of NAMPT and PAK4 induces anti-tumor effects in platinum-resistant ovarian cancer by suppressing mitochondrial function and expression of genes related to inflammation and DNA repair.

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MMSET regulates transcription factors critical for survival of t(4;14) myeloma myeloma cells

Project description:Multiple myeloma (MM) is characterized by recurrent chromosomal translocations. The multiple myeloma SET domain (MMSET), identified by its fusion to the IgH locus in t(4;14) MM, is universally overexpressed and has been suggested to play an important role in tumorigenicity in t(4;14) MM. In order to identify downstream functional targets of MMSET, we knocked down MMSET expression with shRNAs in KMS11, a t(4;14) MM cell line, and identified differentially expressed genes by gene expression microarray analysis.

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Project description:CRISPR knockout screening on MOLM-13 cells with KPT-9274

2021-01-27 | GSE162473 | GEO

Characterization of the PAK4 interactome by quantitative mass spectrometry

Project description:p21-activated kinase 4 (PAK4) is a serine/threonine kinase critical during development and with a proposed role in cancer and related cellular processes, including cell proliferation, survival and migration. However, while a limited number of PAK4-interacting proteins have been identified, the PAK4 interactome has not been systematically characterized. Here, we employed iTRAQ-based quantitative mass spectrometry of PAK4-immunioprecipitations from three distinct isolated cellular fractions to comprehensively profile the PAK4 interactome in human. These data will provide a valuable resource for further investigations on the role of PAK4 in physiology and disease.

2018-10-27 | PXD004086 | Pride

NSD2 interacts with SMARCA2 and regulates expression of oncogenes CCND1 and PRL3 in t(4;14) multiple myeloma

Project description:Recurrent chromosomal translocations are central to the pathogenesis of multiple myeloma (MM), with t(4;14) translocation being the second-most common and associated with poor prognosis. The nuclear receptor-binding SET domain 2 (NSD2) is overexpressed as a result of the translocation and has been suggested to be the primary oncogenic factor in t(4;14) MM. However, the detailed oncogenic mechanism of NSD2 in MM is still not completely understood. To address the relevant pathways downstream of NSD2 that contributes to myelomagenesis, SILAC-based mass-spectrometry analysis was used to determine NSD2-interacting proteins. We identified 74 proteins and in silico analysis showed that one of them, SMARCA2, interacts with NSD2. Comparison of SMARCA2 expression across MM cell lines with different translocation statuses showed that SMARCA2 was highly expressed in t(4;14) MM cells but not in non-t(4;14) MM cells. SMARCA2 knockdown in t(4;14) MM cells showed reduced cell growth and capacity to form colonies. We further investigated how NSD2 and SMARCA2 regulate the expressions of key myeloma genes, such as PRL3 and CCND1. This study reveals a spectrum of NSD2-interacting proteins involved in different biological pathways, indicating the importance of NSD2 in t(4;14) MM. The interaction between NSD2 and SMARCA2 in regulating the expression of CCND1 and PRL3 suggests the potential of SMARCA2 as a novel therapeutic target for t(4;14) MM.

2021-07-15 | GSE140860 | GEO

MMSET I acts as an oncoprotein and regulates GLO1 expression in t(4;14) multiple myeloma cells

Project description:Multiple myeloma (MM) is characterized by recurrent chromosomal translocations. The translocation t(4;14)(p16;q32) is one of the most common translocation in MMs, affecting 15% of patients, and is associated with very poor prognosis. The histone methyltransferase (HMTase) MMSET is universally overexpressed in t(4;14) MM as a result of the t(4;14) translocation. MMSET is capable of producing 3 major isoforms, the full length MMSET II, short isoforms REIIBP and MMSET I. MMSET II has been suggested to play an important tumorigenic role in t(4;14) MM, but little is yet known about whether and how the MMSET short isoforms contribute to MM tumorigenesis. The aim of this study is to characterize MMSET I roles and determine its downstream targets in t(4;14) MM. In t(4;14) MM cells MMSET I knockdown with shRNAs induced cell apoptosis, reduced colony formation and inhibited tumorigenicity in vivo. We also found MMSET I knockdown decreased GLO1 expression, and ectopic MMSET I increased GLO1 expression, suggesting that MMSET I is an upstream regulator of GLO1. Further analysis indicated that MMSET I bound to GLO1 promoter region and depended on its C-terminus to regulate GLO1 expression. Our preliminary data suggested that MMSET I is an oncoprotein and could regulate GLO1 expression in t(4;14) multiple myeloma cells.

2019-01-01 | GSE98433 | GEO

A novel non-coding RNA within WHSC1 is over-expressed in t(4;14)-positive multiple myeloma and other cancers

Project description:We designed oligonucleotide tiling arrays spanning the t(4;14) breakpoint region on chromosome 4 to identify additional oncogenic RNAs in an unbiased fashion. Four (4) multiple myeloma bone marrow samples with t(4;14) and twelve (12) MM BM samples without t(4;14) were analyzed. Furthermore, seven (7) bladder (1 normal, 6 malignant), eight (8) colon (1 normal, 7 malignant) and eight (8) esophagus (2 normal, 6 maligant) tissue samples were analyzed. Finally, five (5) multiple myeloma cell line samples with t(4;14) - three (3) of LP-1 and two (2) of H929 - and three (3) MM cell line samples and three (3) non-MM cell line samples without t(4;14) - three (3) of U266 and three (3) of Hela - were analyzed.

2012-07-01 | E-GEOD-36685 | biostudies-arrayexpress

Effects of MMSET on gene expression in multiple myeloma

Project description:The MMSET (Multiple Myeloma SET domain) protein is overexpressed in multiple myeloma patients with the translocation t(4;14). Although studies have shown the involvement of MMSET/WHSC1 in development, its mode of action in the pathogenesis of multiple myeloma (MM) is largely unknown. We found that MMSET is a major regulator of chromatin structure and transcription in t(4;14) MM cells. High levels of MMSET correlate with an increase in lysine 36 methylation of histone H3 and a decrease in lysine 27 methylation across the genome, leading to a more open structural state of the chromatin. Loss of MMSET expression alters adhesion properties, suppresses growth and induces apoptosis in MM cells. Consequently, genes affected by high levels of MMSET are implicated in the p53 pathway, cell cycle regulation and integrin signaling. Regulation of many of these genes required functional histone methyl-transferase (HMT) activity of MMSET. These results implicate MMSET as a major epigenetic regulator in t(4;14)+ MM.

2010-10-20 | GSE24746 | GEO

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