NEK2 mediates ALDH1A1-dependent drug resistance in multiple myeloma

Yang, Ye; Zhou, Wen; Xia, Jiliang; Gu, Zhimin; Wendlandt, Erik; Zhan, Xin; Janz, Siegfried; Tricot, Guido; Zhan, Fenghuang

doi:10.18632/oncotarget.2388

Cited by 57 publications

(46 citation statements)

References 44 publications

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“…58 Finally, NEK2 regulates centrosome disjunction/splitting and is highly correlated with drug resistance, rapid relapse, and poor outcome in MM and many other cancers. 47,59 All these data indicate that activity of the APRIL/BCMA pathway plays a central role in MM pathogenesis.…”

Section: Discussionmentioning

confidence: 93%

APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment

Tai

Acharya

et al. 2016

Blood

263

242

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Here we show that overexpression or activation of B-cell maturation antigen (BCMA) by its ligand, a proliferation-inducing ligand (APRIL), promotes human multiple myeloma (MM) progression in vivo. BCMA downregulation strongly decreases viability and MM colony formation; conversely, BCMA overexpression augments MM cell growth and survival via induction of protein kinase B (AKT), MAPK, and nuclear factor (NF)-κB signaling cascades. Importantly, BCMA promotes in vivo growth of xenografted MM cells harboring p53 mutation in mice. BCMA-overexpressing tumors exhibit significantly increased CD31/microvessel density and vascular endothelial growth factor compared with paired control tumors. These tumors also express increased transcripts crucial for osteoclast activation, adhesion, and angiogenesis/metastasis, as well as genes mediating immune inhibition including programmed death ligand 1, transforming growth factor β, and interleukin 10. These target genes are consistently induced by paracrine APRIL binding to BCMA on MM cells, which is blocked by an antagonistic anti-APRIL monoclonal antibody hAPRIL01A (01A). 01A is cytotoxic against MM cells even in the presence of protective bone marrow (BM) myeloid cells including osteoclasts, macrophages, and plasmacytoid dendritic cells. 01A further decreases APRIL-induced adhesion and migration of MM cells via blockade of canonical and noncanonical NF-κB pathways. Moreover, 01A prevents in vivo MM cell growth within implanted human bone chips in SCID mice. Finally, the effect of 01A on MM cell viability is enhanced by lenalidomide and bortezomib. Taken together, these data delineate new molecular mechanisms of in vivo MM growth and immunosuppression critically dependent on BCMA and APRIL in the BM microenvironment, further supporting targeting this prominent pathway in MM

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Section: Discussionmentioning

confidence: 93%

APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment

Tai

Acharya

et al. 2016

Blood

263

242

View full text Add to dashboard Cite

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“…Clonogenic growth was performed as previous reported (25). Briefly, 10,000 myeloma cells were plated in 0.5 mL 0.33% agar/RPMI 1640 (Invitrogen) supplemented with 10% FBS.…”

Section: Methodsmentioning

confidence: 99%

Decreased Ferroportin Promotes Myeloma Cell Growth and Osteoclast Differentiation

Wang

Xia

et al. 2015

Cancer Research

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Iron homeostasis is disrupted in multiple myeloma, a difficult-to-cure plasma cell malignancy with lytic bone lesions. Here, we systematically analyzed iron gene expression signature and demonstrated that mRNA expression of iron exporter ferroportin (FPN1) is significantly downregulated in myeloma cells and correlates negatively with clinic outcome. Restoring expression of FPN1 reduces intracellular liable iron pool, inhibits STAT3-MCL-1 signaling, and suppresses myeloma cells growth. Furthermore, we demonstrated that mRNA of FPN1 is also downregulated at the initial stages of osteoclast differentiation and suppresses myeloma cell–induced osteoclast differentiation through regulating iron regulator TFRC, NF-κB, and JNK pathways. Altogether, we demonstrated that downregulation of FPN1 plays critical roles in promoting myeloma cell growth and bone resorption in multiple myeloma.

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“…A total of 29 of 285 genes that were associated with MM were located in chr 9 [23-31]. Gene gain and loss in chr 9 were analyzed and compared according to drug response, and it was observed that KMS-12-BM, which is resistant to BTZ, showed an increase of CNAs after BTZ treatment (Table 3).…”

Section: Resultsmentioning

confidence: 99%

Chromothripsis in Treatment Resistance in Multiple Myeloma

Lee

Yoon

et al. 2017

Genomics Inform

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Multiple myeloma (MM) is a malignant disease caused by an abnormal proliferation of plasma cells, of which the prognostic factors include chromosomal abnormality, β-2 microglobulin, and albumin. Recently, the term chromothripsis has emerged, which is the massive but highly localized chromosomal rearrangement in response to a one-step catastrophic event. Many studies have shown an association of chromothripsis with the prognosis in several cancers; however, few studies have investigated it in MM. Here, we studied the association between chromothripsis-like patterns and treatment resistance or prognosis. First, we analyzed nine MM cell lines (U266, MM.1S, RPMI8226, KMS-11, KMS-12-BM, KMS-12-PE, KMS-28-BM, KMS-28-PE, and NCI-H929) and bone marrow samples of four patients who were diagnosed with MM by next-generation sequencing-based copy number variation analysis. The frequency of the chromothripsis-like pattern was observed in seven cell lines. We analyzed the treatment-induced chromothripsis-like patterns in KMS-12-BM and KMS-12-PE cells. As a result, breakpoints and chromothripsis-like patterns were increased after drug treatment in the relatively resistant KMS-12-BM. We further analyzed the patients’ results according to the therapeutic response, which was divided into sensitive and resistant, as suggested by the International Myeloma Working Group. The chromothripsis-like pattern was more frequently observed in the resistant group. In the sensitive group, the frequency of the chromothripsis-like pattern decreased after treatment, whereas the resistant group showed increased chromothripsis-like patterns after the treatment. These results suggest that the chromothripsis-like pattern is associated with treatment response in MM.

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NEK2 mediates ALDH1A1-dependent drug resistance in multiple myeloma

Cited by 57 publications

References 44 publications

APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment

APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment

Decreased Ferroportin Promotes Myeloma Cell Growth and Osteoclast Differentiation

Chromothripsis in Treatment Resistance in Multiple Myeloma

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