Rate of CRL4CRBN substrate Ikaros and Aiolos degradation underlies differential activity of lenalidomide and pomalidomide in multiple myeloma cells by regulation of c-Myc and IRF4

Bjorklund, Chad C.; Lu, Ling; Kang, Jian; Hagner, Patrick R.; Havens, Courtney G.; Amatangelo, Michael; Wang, M; Ren, Yan; Couto, Suzana; Breider, M A; Ning, Yuhong; Gandhi, Anita K.; Daniel, Tom; Chopra, Rajesh; Klippel, Anke; Thakurta, Anjan

doi:10.1038/bcj.2015.66

Cited by 175 publications

(167 citation statements)

References 33 publications

(68 reference statements)

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“…Moreover, IRF4 is highly expressed in BMMCs, 9 leading to an antiapoptotic phenotype in myeloma cells. Therefore, immunomodulatory drugs, such as lenalidomide and pomalidomide, which target the Ikaros-IRF4 pathway, would be effective for these cells, [42][43][44][45] but not for myeloma cells that express lower levels of IRF4, such as HNMCs. Accordingly, to achieve full remission, treatments that target different molecules mainly present in BMMCs and HNMCs will be necessary.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-inducible KDM3A addiction in multiple myeloma

et al. 2018

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Key Points• Under hypoxia, KDM3A, but not IRF4, leads myeloma cells to acquire an antiapoptotic phenotype.• KDM3A regulates a long noncoding RNA, MALAT1, leading to upregulation of glycolytic genes under hypoxia.In multiple myeloma (MM), the bone marrow (BM) microenvironment may contain a myeloma cell fraction that has acquired treatment resistance by undergoing an epigenetic gene expression change. Hypoxic stress is an important factor in the BM microenvironment.Recently, we demonstrated that miR-210 was upregulated in hypoxia and downregulated IRF4, which is known as an essential factor in myeloma oncogenesis in normoxia. In the study, we demonstrated that myeloma cells still showed a strong antiapoptotic phenotype despite IRF4 downregulation, suggesting that another antiapoptotic factor might be involved under hypoxic stress. To determine the factor or factors, we conducted gene expression analysis on myeloma cells (primary samples and cell lines) that were exposed to chronic hypoxia and observed upregulation of glycolytic genes and genes encoding H3K9 demethylases in myeloma cells with hypoxia. Among these, KDM3A was most significantly upregulated in all examined cells, and its knockdown induced apoptosis of myeloma cells in chronic hypoxia.Expression of KDM3A was dependent on HIF-1a, which is a transcription factor specifically upregulated in hypoxia. We further demonstrated that an essential target of KDM3A was a noncoding gene, MALAT1, whose upregulation contributed to acquisition of an antiapoptotic phenotype by accumulation of HIF-1a, leading to upregulation of glycolytic genes under hypoxia. This process was independent from IRF4. These results led us to conclude that the hypoxia-inducible HIF-1a-KDM3A-MALAT1 axis also contributes to acquisition of the antiapoptotic phenotype via upregulation of glycolysis-promoting genes. Thus, this axis is a promising therapeutic target against myeloma cells in the BM microenvironment.

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Section: Discussionmentioning

confidence: 99%

Hypoxia-inducible KDM3A addiction in multiple myeloma

et al. 2018

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“…8C), the teratogenic molecule that has been repurposed in lymphoma and leprosy treatments (349,350). Binding of thalidomide and more recently derived CRBN-binding "immunomodulatory" molecules, such as lenalidomide and pomalidomide, switches the ligand binding preference of CRBN from substrates such as MEIS2 to substrates such as the hematopoietic transcription factors Ikaros and Aiolos, thereby reducing cell division (351). Lenalidomidebound CRBN also targets the E3 ligase to CK1a, which contributes to the clinical efficacy of this drug in 5q-deletion associated myelodysplastic syndrome [del(5q) MDS] (352).…”

Section: Kip1mentioning

confidence: 99%

Degrons in cancer

et al. 2017

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Degrons are the elements that are used by E3 ubiquitin ligases to target proteins for degradation. Most degrons are short linear motifs embedded within the sequences of modular proteins. As regulatory sites for protein abundance, they are important for many different cellular processes, such as progression through the cell cycle and monitoring cellular hypoxia. Degrons enable the elimination of proteins that are no longer required, preventing their possible dysfunction. Although the human genome encodes~600 E3 ubiquitin ligases, only a fraction of these enzymes have well-defined target degrons. Thus, for most cellular proteins, the destruction mechanisms are poorly understood. This is important for many diseases, especially for cancer, a disease that involves the enhanced expression of oncogenes and the persistence of encoded oncoproteins coupled with reduced abundance of tumor suppressors. Lossof-function mutations occur in the degrons of several oncoproteins, such as the transcription factors MYC and NRF2, and in various mitogenic receptors, such as NOTCH1 and several receptor tyrosine kinases. Mutations eliminating the function of the b-catenin degron are found in many cancers and are considered one of the most abundant mutations driving carcinogenesis. In this Review, we describe the current knowledge of degrons in cancer and suggest that increased research on the "dark degrome" (unknown degron-E3 relationships) would enhance progress in cancer research.

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“…The direct tumoricidal effects of lenalidomide are mediated in myeloma cells by targeting cereblon, a component of the E3 ubiquitin ligase complex. [1][2][3][4] This interaction triggers proteasome degradation of transcription factors Ikaros and Aiolos, resulting in downregulation of myeloma survival signals IRF4 and MYC and upregulation of the immunoregulatory molecule interleukin 2. 2,4,5 Synergistic effects are observed when lenalidomide is administered in combination with dexamethasone, making this regimen one of the standards of care in patients with newly diagnosed and relapsed multiple myeloma.…”

Section: Introductionmentioning

confidence: 99%

“…[1][2][3][4] This interaction triggers proteasome degradation of transcription factors Ikaros and Aiolos, resulting in downregulation of myeloma survival signals IRF4 and MYC and upregulation of the immunoregulatory molecule interleukin 2. 2,4,5 Synergistic effects are observed when lenalidomide is administered in combination with dexamethasone, making this regimen one of the standards of care in patients with newly diagnosed and relapsed multiple myeloma. [6][7][8][9][10][11] Lenalidomide and low-dose dexamethasone (Rd) and melphalan plus prednisone and thalidomide (MPT) are 2 treatment options for patients with newly diagnosed multiple myeloma (NDMM) ineligible for autologous stem cell transplant.…”

Section: Introductionmentioning

confidence: 99%