Leflunomide regulates c-Myc expression in myeloma cells through PIM targeting

Buettner, Ralf; Morales, Corey; Caserta, Enrico; Troadec, Estelle; Gunes, Emine Gulsen; Viola, Domenico; Khalife, Jihane; Li, Hongzhi; Christofferson, Austin; Wu, Xiwei; Synold, Timothy W.; Palmer, Joycelynne; Sanchez, James F.; Pozhitkov, Alexander; Vaidehi, Nagarajan; Marcucci, Guido; Krishnan, Amrita; Rosenzweig, Michael; Pichiorri, Flavia; Rosen, Steven T.

doi:10.1182/bloodadvances.2018027227

Cited by 14 publications

(16 citation statements)

References 24 publications

(26 reference statements)

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“…RNA sequencing (RNA-seq), RNA expression analysis and gene set enrichment analysis (GSEA) were performed as described previously [ 25 ] where the fatty acid metabolism and oxidative phosphorylation metabolism gene sets, containing 120 and 180 genes, respectively, were from the Molecular Signatures Database (MSigDB) Hallmark gene sets. The top 10 globally enriched pathways after GSEA analysis in each comparison were presented in a bubble plot, where color represents the significance, and the size the number of involved differentially expressed (DE) genes.…”

Section: Methodsmentioning

confidence: 99%

Targeting the metabolic vulnerability of acute myeloid leukemia blasts with a combination of venetoclax and 8-chloro-adenosine

et al. 2021

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Background BCL‐2 inhibition through venetoclax (VEN) targets acute myeloid leukemia (AML) blast cells and leukemic stem cells (LSCs). Although VEN-containing regimens yield 60–70% clinical response rates, the vast majority of patients inevitably suffer disease relapse, likely because of the persistence of drug-resistant LSCs. We previously reported preclinical activity of the ribonucleoside analog 8-chloro-adenosine (8-Cl-Ado) against AML blast cells and LSCs. Moreover, our ongoing phase I clinical trial of 8-Cl-Ado in patients with refractory/relapsed AML demonstrates encouraging clinical benefit. Of note, LSCs uniquely depend on amino acid-driven and/or fatty acid oxidation (FAO)-driven oxidative phosphorylation (OXPHOS) for survival. VEN inhibits OXPHOS in LSCs, which eventually may escape the antileukemic activity of this drug. FAO is activated in LSCs isolated from patients with relapsed AML. Methods Using AML cell lines and LSC-enriched blast cells from pre-treatment AML patients, we evaluated the effects of 8-Cl-Ado, VEN and the 8-Cl-Ado/VEN combination on fatty acid metabolism, glycolysis and OXPHOS using liquid scintillation counting, a Seahorse XF Analyzer and gene set enrichment analysis (GSEA). Western blotting was used to validate results from GSEA. HPLC was used to measure intracellular accumulation of 8-Cl-ATP, the cytotoxic metabolite of 8-Cl-Ado. To quantify drug synergy, we created combination index plots using CompuSyn software. The log-rank Kaplan–Meier survival test was used to compare the survival distributions of the different treatment groups in a xenograft mouse model of AML. Results We here report that VEN and 8-Cl-Ado synergistically inhibited in vitro growth of AML cells. Furthermore, immunodeficient mice engrafted with MV4-11-Luc AML cells and treated with the combination of VEN plus 8-Cl-Ado had a significantly longer survival than mice treated with either drugs alone (p ≤ 0.006). We show here that 8-Cl-Ado in the LSC-enriched population suppressed FAO by downregulating gene expression of proteins involved in this pathway and significantly inhibited the oxygen consumption rate (OCR), an indicator of OXPHOS. By combining 8-Cl-Ado with VEN, we observed complete inhibition of OCR, suggesting this drug combination cooperates in targeting OXPHOS and the metabolic homeostasis of AML cells. Conclusion Taken together, the results suggest that 8-Cl-Ado enhances the antileukemic activity of VEN and that this combination represents a promising therapeutic regimen for treatment of AML.

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Section: Methodsmentioning

confidence: 99%

Targeting the metabolic vulnerability of acute myeloid leukemia blasts with a combination of venetoclax and 8-chloro-adenosine

et al. 2021

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“…Additionally, leflunomide, an agent approved for the treatment of the rheumatoid arthritis, also exhibits anti-myeloma activity through the downregulation of MYC protein in preclinical studies [ 80 ]. Leflunomide blocks the PIM family, which stabilizes MYC, and on the other hand, its active metabolite teriflunomide induces the proteasome degradation of MYC.…”

Section: Genetic Abnormalitiesmentioning

confidence: 99%

“…Leflunomide blocks the PIM family, which stabilizes MYC, and on the other hand, its active metabolite teriflunomide induces the proteasome degradation of MYC. Moreover, leflunomide in combination with lenalidomide inhibits cell growth [ 80 ]. A phase 2 trial with leflunomide in combination with pomalidomide and dexamethasone is currently underway.…”

Section: Genetic Abnormalitiesmentioning

confidence: 99%

Genetic Abnormalities in Multiple Myeloma: Prognostic and Therapeutic Implications

Cardona‐Benavides

Ramón

Gutiérrez

2021

Cells

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Some genetic abnormalities of multiple myeloma (MM) detected more than two decades ago remain major prognostic factors. In recent years, the introduction of cutting-edge genomic methodologies has enabled the extensive deciphering of genomic events in MM. Although none of the alterations newly discovered have significantly improved the stratification of the outcome of patients with MM, some of them, point mutations in particular, are promising targets for the development of personalized medicine. This review summarizes the main genetic abnormalities described in MM together with their prognostic impact, and the therapeutic approaches potentially aimed at abrogating the undesirable pathogenic effect of each alteration.

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“…Furthermore, teriflunomide synergized Gemcitabine-induced growth inhibition of pancreatic cancer cells through PIM kinase-dependent inhibition of the c-myc tumorigenic signaling pathway [77] . Teriflunomide directly inhibits the entire PIM family, especially PIM-3 and PIM-1 [78] . Likewise, teriflunomide suppressed the proliferation of the murine leukemia cell line LSTRA through inhibition of the tyrosine kinase activity of p56 lck [79] .…”

Section: Pharmacodynamics Of Lfmentioning

confidence: 99%

“…This may be true despite the protein tyrosine kinase inhibitory action, which was found to be of additional benefit. LF and its congeners are investigated in different in vitro and in vivo models of cancer including prostate [9] , [32] , [107] , breast [34] , neuroblastoma [8] , [108] , multiple myeloma [78] , [109] , [110] , thyroid [33] , leukemia [111] , [112] , and lymphoma [113] Table 2 .…”

Section: Clinical Importance Of Lfmentioning

confidence: 99%

Leflunomide an immunomodulator with antineoplastic and antiviral potentials but drug-induced liver injury: A comprehensive review

Alamri

Elmeligy

Albalawi

et al. 2021

International Immunopharmacology

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Leflunomide (LF) represents the prototype member of dihydroorotate dehydrogenase (DHODH) enzyme inhibitors. DHODH is a mitochondrial inner membrane enzyme responsible for catalytic conversion of dihydroorotate into orotate, a rate-limiting step in the de novo synthesis of the pyrimidine nucleotides. LF produces cellular depletion of pyrimidine nucleotides required for cell growth and proliferation. Based on the affected cells the outcome can be attainable as immunosuppression, antiproliferative, and/or the recently gained attention of the antiviral potentials of LF and its new congeners. Also, protein tyrosine kinase inhibition is an additional mechanistic benefit of LF, which inhibits immunological events such as cellular expansion and immunoglobulin production with an enhanced release of immunosuppressant cytokines. LF is approved for the treatment of autoimmune arthritis of rheumatoid and psoriatic pathogenesis. Also, LF has been used off-label for the treatment of relapsing-remitting multiple sclerosis. However, LF antiviral activity is repurposed and under investigation with related compounds under a phase-I trial as a SARS CoV-2 antiviral in cases with COVID-19. Despite success in improving patients’ mobility and reducing joint destruction, reported events of LF-induced liver injury necessitated regulatory precautions. LF should not be used in patients with hepatic impairment or in combination with drugs elaborating a burden on the liver without regular monitoring of liver enzymes and serum bilirubin as safety biomarkers. This study aims to review the pharmacological and safety profile of LF with a focus on the LF-induced hepatic injury from the perspective of pathophysiology and possible protective agents.

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Leflunomide regulates c-Myc expression in myeloma cells through PIM targeting

Abstract: Key Points Teriflunomide, the active metabolite of leflunomide, downregulates c-Myc expression through inhibition of PIM kinases. Leflunomide together with lenalidomide significantly extended survival in an in vivo MM model.

Cited by 14 publications

References 24 publications

Targeting the metabolic vulnerability of acute myeloid leukemia blasts with a combination of venetoclax and 8-chloro-adenosine

Targeting the metabolic vulnerability of acute myeloid leukemia blasts with a combination of venetoclax and 8-chloro-adenosine

Genetic Abnormalities in Multiple Myeloma: Prognostic and Therapeutic Implications

Leflunomide an immunomodulator with antineoplastic and antiviral potentials but drug-induced liver injury: A comprehensive review

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