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MYC is an oncogenic transcription factor dysregulated in about half of total human tumors. Transcriptomic studies reveal more than 1000 genes regulated by MYC but a much smaller fraction of genes is directly transactivated by MYC. Virtually all Burkitt lymphoma (BL) carry chromosomal translocations involving MYC oncogene. All endemic BL and a fraction of sporadic BL are associated to Epstein-Barr virus (EBV) infection. The currently accepted mechanism is that EBV is the lymphoma causing agent inducing MYC translocation. Herein we show that the EBV receptor gene, CR2 (or CD21), is a bona fide direct MYC target gene. This is based on several evidences: MYC induces CR2 expression in both proliferating and arrested cells, binds the human CR2 promoter and transactivates CR2 in an E-box dependent manner and in the absence of protein synthesis. Moreover, using mice with conditional MYC ablation we show that MYC induces CR2 in primary B cells. Importantly, MYC silencing or MYC overexpression in BL cells results in less and more efficient EBV infection, respectively. Altogether, in contrast to the widely accepted mechanism for the correlation between EBV and endemic BL, we propose an alternative mechanism in which MYC dysregulation occurs first and favors the EBV infection.

The molecular hallmark of Burkitt lymphoma (BL) is a chromosomal translocation that results in deregulated expression ofMYConcogene. This translocation is present in virtually all BL. MYC is an oncogenic transcription factor deregulated in about half of total human tumors, by translocation or other mechanisms. Transcriptomic studies reveal more than 1000 genes regulated by MYC but a much smaller fraction of these genes is directly activated by MYC. All the endemic BL and many sporadic BL cells are associated to the Epstein-Barr virus (EBV) infection. The currently accepted mechanism for the MYC and BL association is that EBV is the causing agent inducing MYC translocation. Complement receptor 2 or CR2 (also called CD21) is a membrane protein that serves as EBV receptor in lymphoid cells. Here we show that CR2 is a direct MYC target gene. This conclusion is based on several evidences. First, MYC downregulation is linked toCR2downregulation both in proliferating and in arrested cells. Second, MYC binds humanCR2promoter and this binding depends on E-box elements. Third, MYC activatesCR2promoter in an E-box dependent manner. Four, MYC activatesCR2transcription in the absence of protein synthesis. Importantly, MYC also inducesCR2expression in mouse primary B cells. Thus, CR2 is abona fideMYC direct target gene. Moreover, higher MYC expression levels in Burkitt lymphoma-derived cells result in a more efficient EBV infection. We propose an alternative mechanism compatible with the correlation between EBV infection and MYC translocation observed in endemic BL, i.e., that deregulated MYC in BL cells occurs first and favors the EBV infection.

© 2021 The Author(s)., Chronic myelogenous leukemia (CML) is a hematological malignancy that highly depends on the BCR-ABL1/STAT5 signaling pathway for cell survival. First-line treatments for CML consist of tyrosine kinase inhibitors that efficiently target BCR-ABL1 activity. However, drug resistance and intolerance are still therapeutic limitations in Ph+ cells. Therefore, the development of new anti-CML drugs that exhibit alternative mechanisms to overcome these limitations is a desirable goal. In this work, the antitumoral activity of JKST6, a naphthoquinone-pyrone hybrid, was assessed in imatinib-sensitive and imatinib-resistant human CML cells. Live-cell imaging analysis revealed JKST6 potent antiproliferative activity in 2D and 3D CML cultures. JKST6 provoked cell increase in the subG1 phase along with a reduction in the G0/G1 phase and altered the expression of key proteins involved in the control of mitosis and DNA damage. Rapid increases in Annexin V staining and activation/cleavage of caspases 8, 9 and 3 were observed after JKST6 treatment in CML cells. Of interest, JKST6 inhibited BCR-ABL1/STAT5 signaling through oncokinase downregulation that was preceded by rapid polyubiquitination. In addition, JKST6 caused a transient increase in JNK and AKT phosphorylation, whereas the phosphorylation of P38-MAPK and Src was reduced. Combinatory treatment unveiled synergistic effects between imatinib and JKST6. Notably, JKST6 maintained its antitumor efficacy in BCR-ABL1-T315I-positive cells and CML cells that overexpress BCR-ABL and even restored imatinib efficacy after a short exposure time. These findings, together with the observed low toxicity of JKST6, reveal a novel multikinase modulator that might overcome the limitations of BCR-ABL1 inhibitors in CML therapy., This research has been funded by Spanish Ministry of Economy and Competitiveness - MINECO - (SAF 2015–65113-C2–1-R and RTI2018–094356-B-C21 to AEB, SAF2015–65113-C2–2 to LFP, SAF2017–88026-R to JL) with the co-funding of European Regional Development Fund (EU-ERDF), Canary Islands Government (CEI2018–23/ACIISI to BG, CEI2019–08/ACIISI to BG and LFP, ProID2021010037 to AEB, LFP and BG) and "Juan de la Cierva Incorporacion" Grant Program from the Ministry of Science, Innovation and Universities (IJC2018-035193-I to CR). This project has been also supported by Alfredo Martin-Reyes Foundation (Arehucas)-Canary Islands Foundation for Cancer Research (FICIC). HAT is recipient of a predoctoral program grant from ULPGC (2016). JCM was funded by the Instituto de Salud Carlos III through a Miguel Servet program (CPII17/00015).