ARNT/HIF-1β links high-risk 1q21 gain and microenvironmental hypoxia to drug resistance and poor prognosis in multiple myeloma

Chuan Wu, Ting Yang, Yingmin Liu, Yicheng Lu, Yanping Yang, Xiaobo Liu, Xuelian Liu, Long Ye, Yue Sun, Xue Wang, Qingchao Li, Peiyu Yang, Xiaoyuan Yu, Sujun Gao, Shaji K Kumar, Fengyan Jin, Yun Dai, Wei Li

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

1q21 gain is a common cytogenetic abnormality featuring high-risk multiple myeloma (HRMM). However, the molecular mechanism underlying the adverse prognostic effect of 1q21 gain remains largely unclear. Here, we report that ARNT/HIF-1β, a 1q21 gene, is highly expressed in HRMM and induced by microenvironmental hypoxia, which confers drug resistance and correlates with inferior outcome. Analysis of the gene expression profile database revealed that ARNT expression was upregulated in MM and increased with disease progression or in HRMM subtypes (particularly 1q21 gain), while correlated to shorter overall survival. In a cohort of 40 MM patients, qPCR further validated that ARNT expression was higher in MM patients than normal donors. MM cells carrying 1q21 gain or acquired drug resistance displayed a robust increase in HIF-1β protein level. Hypoxia induced HIF-1β expression via a NF-κB-dependent process. Notably, HIF-1β overexpression impaired bortezomib sensitivity, whereas shRNA knockdown of ARNT reversed hypoxia-mediated drug resistance. Together, these findings suggest that ARNT/HIF-1β might represent a novel biomarker for risk stratification and prognosis of HRMM patients, as well as a potential therapeutic target for overcoming 1q21 gain- or microenvironment-mediated and acquired drug resistance in MM.

Original languageEnglish (US)
Pages (from-to)3899-3911
Number of pages13
JournalCancer Medicine
Volume7
Issue number8
DOIs
StatePublished - Aug 1 2018
Externally publishedYes

Fingerprint

Multiple Myeloma
Drug Resistance
Transcriptome
Chromosome Aberrations
Small Interfering RNA
Disease Progression
Biomarkers
Hypoxia
Tissue Donors
Databases
Survival
Genes
Proteins
Therapeutics

Keywords

  • 1q21 gain
  • ARNT/HIF-1β
  • drug resistance
  • hypoxia
  • multiple myeloma

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

Cite this

ARNT/HIF-1β links high-risk 1q21 gain and microenvironmental hypoxia to drug resistance and poor prognosis in multiple myeloma. / Wu, Chuan; Yang, Ting; Liu, Yingmin; Lu, Yicheng; Yang, Yanping; Liu, Xiaobo; Liu, Xuelian; Ye, Long; Sun, Yue; Wang, Xue; Li, Qingchao; Yang, Peiyu; Yu, Xiaoyuan; Gao, Sujun; Kumar, Shaji K; Jin, Fengyan; Dai, Yun; Li, Wei.

In: Cancer Medicine, Vol. 7, No. 8, 01.08.2018, p. 3899-3911.

Research output: Contribution to journalArticle

Wu, C, Yang, T, Liu, Y, Lu, Y, Yang, Y, Liu, X, Liu, X, Ye, L, Sun, Y, Wang, X, Li, Q, Yang, P, Yu, X, Gao, S, Kumar, SK, Jin, F, Dai, Y & Li, W 2018, 'ARNT/HIF-1β links high-risk 1q21 gain and microenvironmental hypoxia to drug resistance and poor prognosis in multiple myeloma', Cancer Medicine, vol. 7, no. 8, pp. 3899-3911. https://doi.org/10.1002/cam4.1596
Wu, Chuan ; Yang, Ting ; Liu, Yingmin ; Lu, Yicheng ; Yang, Yanping ; Liu, Xiaobo ; Liu, Xuelian ; Ye, Long ; Sun, Yue ; Wang, Xue ; Li, Qingchao ; Yang, Peiyu ; Yu, Xiaoyuan ; Gao, Sujun ; Kumar, Shaji K ; Jin, Fengyan ; Dai, Yun ; Li, Wei. / ARNT/HIF-1β links high-risk 1q21 gain and microenvironmental hypoxia to drug resistance and poor prognosis in multiple myeloma. In: Cancer Medicine. 2018 ; Vol. 7, No. 8. pp. 3899-3911.
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abstract = "1q21 gain is a common cytogenetic abnormality featuring high-risk multiple myeloma (HRMM). However, the molecular mechanism underlying the adverse prognostic effect of 1q21 gain remains largely unclear. Here, we report that ARNT/HIF-1β, a 1q21 gene, is highly expressed in HRMM and induced by microenvironmental hypoxia, which confers drug resistance and correlates with inferior outcome. Analysis of the gene expression profile database revealed that ARNT expression was upregulated in MM and increased with disease progression or in HRMM subtypes (particularly 1q21 gain), while correlated to shorter overall survival. In a cohort of 40 MM patients, qPCR further validated that ARNT expression was higher in MM patients than normal donors. MM cells carrying 1q21 gain or acquired drug resistance displayed a robust increase in HIF-1β protein level. Hypoxia induced HIF-1β expression via a NF-κB-dependent process. Notably, HIF-1β overexpression impaired bortezomib sensitivity, whereas shRNA knockdown of ARNT reversed hypoxia-mediated drug resistance. Together, these findings suggest that ARNT/HIF-1β might represent a novel biomarker for risk stratification and prognosis of HRMM patients, as well as a potential therapeutic target for overcoming 1q21 gain- or microenvironment-mediated and acquired drug resistance in MM.",
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AU - Wu, Chuan

AU - Yang, Ting

AU - Liu, Yingmin

AU - Lu, Yicheng

AU - Yang, Yanping

AU - Liu, Xiaobo

AU - Liu, Xuelian

AU - Ye, Long

AU - Sun, Yue

AU - Wang, Xue

AU - Li, Qingchao

AU - Yang, Peiyu

AU - Yu, Xiaoyuan

AU - Gao, Sujun

AU - Kumar, Shaji K

AU - Jin, Fengyan

AU - Dai, Yun

AU - Li, Wei

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N2 - 1q21 gain is a common cytogenetic abnormality featuring high-risk multiple myeloma (HRMM). However, the molecular mechanism underlying the adverse prognostic effect of 1q21 gain remains largely unclear. Here, we report that ARNT/HIF-1β, a 1q21 gene, is highly expressed in HRMM and induced by microenvironmental hypoxia, which confers drug resistance and correlates with inferior outcome. Analysis of the gene expression profile database revealed that ARNT expression was upregulated in MM and increased with disease progression or in HRMM subtypes (particularly 1q21 gain), while correlated to shorter overall survival. In a cohort of 40 MM patients, qPCR further validated that ARNT expression was higher in MM patients than normal donors. MM cells carrying 1q21 gain or acquired drug resistance displayed a robust increase in HIF-1β protein level. Hypoxia induced HIF-1β expression via a NF-κB-dependent process. Notably, HIF-1β overexpression impaired bortezomib sensitivity, whereas shRNA knockdown of ARNT reversed hypoxia-mediated drug resistance. Together, these findings suggest that ARNT/HIF-1β might represent a novel biomarker for risk stratification and prognosis of HRMM patients, as well as a potential therapeutic target for overcoming 1q21 gain- or microenvironment-mediated and acquired drug resistance in MM.

AB - 1q21 gain is a common cytogenetic abnormality featuring high-risk multiple myeloma (HRMM). However, the molecular mechanism underlying the adverse prognostic effect of 1q21 gain remains largely unclear. Here, we report that ARNT/HIF-1β, a 1q21 gene, is highly expressed in HRMM and induced by microenvironmental hypoxia, which confers drug resistance and correlates with inferior outcome. Analysis of the gene expression profile database revealed that ARNT expression was upregulated in MM and increased with disease progression or in HRMM subtypes (particularly 1q21 gain), while correlated to shorter overall survival. In a cohort of 40 MM patients, qPCR further validated that ARNT expression was higher in MM patients than normal donors. MM cells carrying 1q21 gain or acquired drug resistance displayed a robust increase in HIF-1β protein level. Hypoxia induced HIF-1β expression via a NF-κB-dependent process. Notably, HIF-1β overexpression impaired bortezomib sensitivity, whereas shRNA knockdown of ARNT reversed hypoxia-mediated drug resistance. Together, these findings suggest that ARNT/HIF-1β might represent a novel biomarker for risk stratification and prognosis of HRMM patients, as well as a potential therapeutic target for overcoming 1q21 gain- or microenvironment-mediated and acquired drug resistance in MM.

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