<i><scp>ARNT</scp></i>/<scp>HIF</scp>‐1β links high‐risk 1q21 gain and microenvironmental hypoxia to drug resistance and poor prognosis in multiple myeloma

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

doi:10.1002/cam4.1596

Cited by 31 publications

(30 citation statements)

References 52 publications

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“…Another possible cause of instability is the overexpression of the chromatin modifying enzymes, such as KDM4A. KDM4A is a histone demethylase, which binds the BCL9 locus and causes the rereplication and site-specific copy number gains of 1q12 and 1q21 43 , altered expression of microRNAs, and selective pressures, such as hypoxic stress 44–46 . The induced gains of 1q12 and 1q21 reported in these studies are not stably inherited but transiently regenerated in subsequent S phases, just as in ICF syndrome and MM.…”

Section: Discussionmentioning

confidence: 99%

An acquired high-risk chromosome instability phenotype in multiple myeloma: Jumping 1q Syndrome

et al. 2019

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Patients with multiple myeloma (MM) accumulate adverse copy number aberrations (CNAs), gains of 1q21, and 17p deletions during disease progression. A subset of these patients develops heightened 1q12 pericentromeric instability and jumping translocations of 1q12 (JT1q12), evidenced by increased copy CNAs of 1q21 and losses in receptor chromosomes (RC). To understand the progression of these aberrations we analyzed metaphase cells of 50 patients with ≥4 CNAs of 1q21 by G-banding, locus specific FISH, and spectral karyotyping. In eight patients with ≥5 CNAs of 1q21 we identified a chromosome instability phenotype similar to that found in ICF syndrome (immunodeficiency, centromeric instability, and facial anomalies). Strikingly, the acquired instability phenotype identified in these patients demonstrates the same transient structural aberrations of 1q12 as those found in ICF syndrome, suggesting similar underlying pathological mechanisms. Four types of clonal aberrations characterize this phenotype including JT1q12s, RC deletions, 1q12-21 breakage-fusion-bridge cycle amplifications, and RC insertions. In addition, recurring transient aberrations include 1q12 decondensation and breakage, triradials, and 1q micronuclei. The acquired self-propagating mobile property of 1q12 satellite DNA drives the continuous regeneration of 1q12 duplication/deletion events. For patients demonstrating this instability phenotype, we propose the term “Jumping 1q Syndrome.”

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Section: Discussionmentioning

confidence: 99%

An acquired high-risk chromosome instability phenotype in multiple myeloma: Jumping 1q Syndrome

et al. 2019

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“…It is suggested that genes located in the 1q21 amplicon, including CKS1B , PSMD4, IL6R, ADAR, MCL1 , and others, are associated with tumor proliferation and/or drug sensitivity because of upregulation of the expressed genes resulting from the increased gene dosage in MM cells with 1q21+ [ 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ]. It has been demonstrated by experimental cellular models, and/ or correlation analysis of gene expression levels and prognosis in a large patient cohort.…”

Section: Introductionmentioning

confidence: 99%

Gain/Amplification of Chromosome Arm 1q21 in Multiple Myeloma

Hanamura

2021

Cancers

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Multiple myeloma (MM), a plasma cell neoplasm, is an incurable hematological malignancy characterized by complex genetic and prognostic heterogeneity. Gain or amplification of chromosome arm 1q21 (1q21+) is the most frequent adverse chromosomal aberration in MM, occurring in 40% of patients at diagnosis. It occurs in a subclone of the tumor as a secondary genomic event and is more amplified as the tumor progresses and a risk factor for the progression from smoldering multiple myeloma to MM. It can be divided into either 1q21 gain (3 copies) or 1q21 amplification (≥4 copies), and it has been suggested that the prognosis is worse in cases of amplification than gain. Trisomy of chromosome 1, jumping whole-arm translocations of chromosome1q, and tandem duplications lead to 1q21+ suggesting that its occurrence is not consistent at the genomic level. Many studies have reported that genes associated with the malignant phenotype of MM are situated on the 1q21 amplicon, including CKS1B, PSMD4, MCL1, ANP32E, and others. In this paper, we review the current knowledge regarding the clinical features, prognostic implications, and the speculated pathology of 1q21+ in MM, which can provide clues for an effective treatment approach to MM patients with 1q21+.

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“…Complete remission (CR) ratio of VTD was lower than those of VRd (38.5% vs. 59%), while the imaging CR ratio of VTD was similar to that of VRd using PET-CT (63.9% vs. 62%) [ 96 , 97 ]. Thus, VTD is considered to be effective for myeloma in hypoxia due to the release of EMD by THAL although hypoxia induces resistance for BOR [ 98 ].…”

Section: Myeloma Cells In Hypoxia and Vascular Nichementioning

confidence: 99%

Treatment Strategies Considering Micro-Environment and Clonal Evolution in Multiple Myeloma

Suzuki

Nishiwaki

Yano

2021

Cancers

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Multiple myeloma is an uncurable hematological malignancy because of obtained drug resistance. Microenvironment and clonal evolution induce myeloma cells to develop de novo and acquired drug resistance, respectively. Cell adhesion-mediated drug resistance, which is induced by the interaction between myeloma and bone marrow stromal cells, and soluble factor-mediated drug resistance, which is induced by cytokines and growth factors, are two types of de novo drug resistance. The microenvironment, including conditions such as hypoxia, vascular and endosteal niches, contributes toward de novo drug resistance. Clonal evolution was associated with acquired drug resistance and classified as branching, linear, and neutral evolutions. The branching evolution is dependent on the microenvironment and escape of immunological surveillance while the linear and neutral evolution is independent of the microenvironment and associated with aggressive recurrence and poor prognosis. Proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), monoclonal antibody agents (MoAbs), and autologous stem cell transplantation (ASCT) have improved prognosis of myeloma via improvement of the microenvironment. The initial treatment plays the most important role considering de novo and acquired drug resistance and should contain PIs, IMIDs, MoAb and ASCT. This review summarizes the role of anti-myeloma agents for microenvironment and clonal evolution and treatment strategies to overcome drug resistance.

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

Cited by 31 publications

References 52 publications

An acquired high-risk chromosome instability phenotype in multiple myeloma: Jumping 1q Syndrome

An acquired high-risk chromosome instability phenotype in multiple myeloma: Jumping 1q Syndrome

Gain/Amplification of Chromosome Arm 1q21 in Multiple Myeloma

Treatment Strategies Considering Micro-Environment and Clonal Evolution in Multiple Myeloma

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