Addiction to c-MYC in multiple myeloma

Holien, Toril; Våtsveen, Thea Kristin; Hella, Hanne; Waage, Anders; Sundan, Anders

doi:10.1182/blood-2011-08-371567

Cited by 156 publications

(153 citation statements)

References 17 publications

(17 reference statements)

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“…The MYC-MAX inhibitor 10054-F4 was effective on human MM cell lines and samples from patients and, although there was not a good correlation between sensitivity and MYC levels, cells expressing the highest levels of MYC tended to be more resistant to the treatment. 64 All these results support the idea that targeting MYC dimerization is feasible. However, it may have the drawback that not all MYC functions depend on MAX.…”

supporting

confidence: 62%

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MYC as therapeutic target in leukemia and lymphoma

Cortiguera¹,

Batlle-López²,

Albajar³

et al. 2015

BLCTT

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MYC is a transcription factor that is involved in the expression of many genes. Deregulated MYC is found in about half of human tumors, being more prevalent in hematological neoplasms. Deregulation mechanisms include chromosomal translocation (particularly in lymphoma), amplification, and hyperactivation of MYC transcription. Here we review MYC involvement in the major types of leukemia and lymphoma. MYC rearrangements appear in all Burkitt lymphomas and are common in other lymphoma types, whereas in acute lymphoblastic leukemia, acute myeloid leukemia, lymphoproliferative, and myeloproferative diseases, they are less frequent. However, MYC overexpression is present in all types of hematological malignancies and often correlates with a worse prognosis. Data in leukemia-derived cells and in animal models of lymphomagenesis and leukemogenesis suggest that MYC would be a good therapeutic target. Several MYC-directed therapies have been assayed in preclinical settings and even in clinical trials. First, peptides and small molecules that interrupt the MYC-MAX interaction impair MYCmediated tumorogenesis in several mouse models of solid tumors, although not yet in lymphoma and leukemia models. Second, there are a number of small molecules inhibiting the interaction of MYC-MAX heterodimers with DNA, still in the preclinical research phase. Third, inhibitors of MYC expression via the inhibition of BRD4 (a reader of acetylated histones) have been shown to control the growth of MYC-transformed leukemia and lymphoma cells and are being used in clinic trials. Finally, we review a number of promising MYC-mediated synthetic lethal approaches that are under study and have been tested in hematopoietic neoplasms.

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supporting

confidence: 62%

“…63 Moreover, MM is one of the neoplasms that respond to treatment with BRD4 inhibitors (see "MYC as a target in leukemia and lymphoma" section), leading to MYC downregulation. 64 …”

Section: Multiple Myelomamentioning

confidence: 99%

MYC as therapeutic target in leukemia and lymphoma

Cortiguera¹,

Batlle-López²,

Albajar³

et al. 2015

BLCTT

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“…All of these proteins are critical for the survival of MM cells. 18,36,37 RSK2 was demonstrated to phosphorylate and regulate C/EBPb, 38 which was reported to control transcription factors critical for survival of MM cells, including IRF4. 39 RSK2 has also been shown to directly regulate proteins involved in apoptosis, such as BAD 40,41 and BIM.…”

Section: Discussionmentioning

confidence: 99%

RNA interference screening identifies lenalidomide sensitizers in multiple myeloma, including RSK2

Zhu

Yin

Bruins

et al. 2015

Blood

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• High-throughput RNAi screening identified lenalidomide sensitizer genes, including RSK2, RAB, peroxisome, and potassium channel family members.• Knockdown or inhibition of RSK2 synergized with lenalidomide to induce myeloma cytotoxicity and downregulation of interferon regulatory factor 4 and MYC.To identify molecular targets that modify sensitivity to lenalidomide, we measured proliferation in multiple myeloma (MM) cells transfected with 27 968 small interfering RNAs in the presence of increasing concentrations of drug and identified 63 genes that enhance activity of lenalidomide upon silencing. Ribosomal protein S6 kinase (RPS6KA3 or RSK2) was the most potent sensitizer. Other notable gene targets included 5 RAB family members, 3 potassium channel proteins, and 2 peroxisome family members. Single genes of interest included I-k-B kinase-a (CHUK), and a phosphorylation dependent transcription factor (CREB1), which associate with RSK2 to regulate several signaling pathways. RSK2 knockdown induced cytotoxicity across a panel of MM cell lines and consistently increased sensitivity to lenalidomide. Accordingly, 3 small molecular inhibitors of RSK2 demonstrated synergy with lenalidomide cytotoxicity in MM cells even in the presence of stromal contact. Both RSK2 knockdown and small molecule inhibition downregulate interferon regulatory factor 4 and MYC, and provides an explanation for the synergy between lenalidomide and RSK2 inhibition. Interestingly, RSK2 inhibition also sensitized MM cells to bortezomib, melphalan, and dexamethasone, but did not downregulate Ikaros or influence lenalidomide-mediated downregulation of tumor necrosis factor-a or increase lenalidomide-induced IL-2 upregulation. In summary, inhibition of RSK2 may prove a broadly useful adjunct to MM therapy. (Blood. 2015;125(3): [483][484][485][486][487][488][489][490][491] IntroductionThe immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide are broadly used in the treatment of patients with multiple myeloma (MM) and have produced significant clinical advances in both newly diagnosed and advanced disease.1,2 However, only 30% of relapsed MM patients respond to single agent IMiD therapy and most patients eventually develop drug resistance. The underlying mechanisms defining this nonresponsiveness are largely unknown. Recently, Cereblon (CRBN) and Ikaros/Aiolos (IZKF1 and IZKF3) were identified as the molecular targets of IMiDs in MM 3-6 via their ability to induce cytotoxicity by inhibiting interferon regulatory factor 4 (IRF4) and MYC. The action of IMiDs appears to be mediated via binding to CRBN with activation of its associated E3 ubiquitin ligase and subsequent proteasomal degradation of Ikaros. 5,6 Furthermore, low CRBN and IZKF1 levels are associated with IMiD resistance, 3,4,7,8 but other parallel pathways or downstream events that enhance or preclude drug responsiveness are unknown.In the present study, a druggable genome short interfering RNA (siRNA) screen was used to identify 63 genes whose loss of expression enhance...

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“…32 Thus, upregulation of CUL4A after lenalidomide treatment may result in the downregulation of Myc and apoptosis because inhibition of Myc activity causes MM cell death. 33 In addition to regulating the turnover of proteins, CUL4A also controls transcription. CUL4 binds to the promoter of a tumorsuppressor gene, CDK inhibitor p16…”

Section: 13mentioning

confidence: 99%

Aiolos collaborates with Blimp-1 to regulate the survival of multiple myeloma cells

Hung

Chen

et al. 2016

Cell Death Differ

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The transcriptional repressor B lymphocyte-induced maturation protein-1 (Blimp-1) has crucial roles in the control of plasma cell differentiation and in maintaining survival of plasma cells. However, how Blimp-1 ensures the survival of plasma cell malignancy, multiple myeloma (MM), has remained elusive. Here we identified Aiolos, an anti-apoptotic transcription factor of MM cells, as a Blimp-1-interacting protein by mass spectrometry. ChIP coupled with DNA microarray was used to profile the global binding of Aiolos and Blimp-1 to endogenous targets in MM cells, which revealed their co-binding to a large number of genes, including apoptosis-related genes. Accordingly, Blimp-1 and Aiolos regulate similar transcriptomes in MM cells. Analysis of the binding motifs for Blimp-1 and Aiolos uncovered a partial motif that was similar across sites for both proteins. Aiolos promotes the binding of Blimp-1 to target genes and thereby enhances Blimp-1-dependent transcriptional repression. Furthermore, treatment with an anti-MM agent, lenalidomide, caused ubiquitination and proteasomal degradation of Blimp-1, leading to the de-repression of a new Blimp-1 direct target, CULLIN 4A (CUL4A), and reduced Aiolos levels. Accordingly, lenalidomide-induced cell death was partially rescued by reintroduction of Blimp-1 or knockdown of CUL4A. Thus, we demonstrated the functional impacts and underlying mechanisms of the interaction between Aiolos and Blimp-1 in maintaining MM cell survival. We also showed that interruption of Blimp-1/Aiolos regulatory pathways contributes to lenalidomide-mediated anti-MM activity.

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Addiction to c-MYC in multiple myeloma

Cited by 156 publications

References 17 publications

MYC as therapeutic target in leukemia and lymphoma

MYC as therapeutic target in leukemia and lymphoma

RNA interference screening identifies lenalidomide sensitizers in multiple myeloma, including RSK2

Aiolos collaborates with Blimp-1 to regulate the survival of multiple myeloma cells

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