Inactivation of the ARF–MDM-2–p53 pathway in sporadic Burkitt's lymphoma in children

Wilda, Monika; Bruch, Jochen; Harder, Lana; Rawer, D; Reiter, Alfred; Borkhardt, Arndt; Woessmann, Wilhelm

doi:10.1038/sj.leu.2403254

Cited by 57 publications

(41 citation statements)

References 35 publications

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“…MYC-driven lymphomagenesis is associated with lesions that bypass the effects of MYC-induced p53 activation, 41 with one third of EmMyc lymphomas 41 and 10% of Burkitt lymphomas 42 (including the Ramos cell line) showing p53 loss or mutation at diagnosis. p53 loss results in chemoresistance and is associated with a poorer prognosis.…”

Section: Bez235-induced Apoptosis Occurs Independently Of P53mentioning

confidence: 99%

Combined inhibition of PI3K-related DNA damage response kinases and mTORC1 induces apoptosis in MYC-driven B-cell lymphomas

Shortt

Martin

Newbold

et al. 2013

Blood

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Key Points• MYC-driven lymphomas demonstrate activation of mTORC1 and an endogenous DNA damage response.• BEZ235 inhibits PI3K-related DNA damage response kinases and mTORC1, inducing p53-independent upregulation of proapoptotic BMF.Pharmacological strategies capable of directly targeting MYC are elusive. Previous studies have shown that MYC-driven lymphomagenesis is associated with mammalian target of rapamycin (mTOR) activation and a MYC-evoked DNA damage response (DDR) transduced by phosphatidylinositol-3-kinase (PI3K)-related kinases (DNA-PK, ATM, and ATR). Here we report that BEZ235, a multitargeted pan-PI3K/dual-mTOR inhibitor, potently killed primary Myc-driven B-cell lymphomas and human cell lines bearing IGcMYC translocations. Using pharmacologic and genetic dissection of PI3K/mTOR signaling, dual DDR/mTORC1 inhibition was identified as a key mediator of apoptosis. Moreover, apoptosis was initiated at drug concentrations insufficient to antagonize PI3K/mTORC2-regulated AKT phosphorylation. p53-independent induction of the proapoptotic BH3-only protein BMF was identified as a mechanism by which dual DDR/mTORC1 inhibition caused lymphoma cell death. BEZ235 treatment induced apoptotic tumor regressions in vivo that correlated with suppression of mTORC1-regulated substrates and reduced H2AX phosphorylation and also with feedback phosphorylation of AKT. These mechanistic studies hold important implications for the use of multitargeted PI3K inhibitors in the treatment of hematologic malignancies. In particular, the newly elucidated role of PI3K-related DDR kinases in response to PI3K inhibitors offers a novel therapeutic opportunity for the treatment of hematologic malignancies with an MYC-driven DDR. (Blood. 2013;121(15):2964-2974

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Section: Bez235-induced Apoptosis Occurs Independently Of P53mentioning

confidence: 99%

Combined inhibition of PI3K-related DNA damage response kinases and mTORC1 induces apoptosis in MYC-driven B-cell lymphomas

Shortt

Martin

Newbold

et al. 2013

Blood

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“…21 We and others earlier investigated the status of MDM2 and p53 in BL cell lines or biopsy samples and found that, in several cases containing wild-type (wt) p53, the function of this protein was compromised by the overexpression of MDM2. 8,22 Finally, another study has shown that p14 ARF , which regulates the function of p53, is frequently altered in BL cell lines carrying wt p53. 23 All these data clearly demonstrate that disruption of the p53 pathway contributes to BL development.…”

Section: Introductionmentioning

confidence: 99%

Activation of p53 by MDM2 antagonists has differential apoptotic effects on Epstein–Barr virus (EBV)-positive and EBV-negative Burkitt's lymphoma cells

et al. 2009

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p53 inactivation is often observed in Burkitt's lymphoma (BL) cells, because of either mutations in p53 gene or an overexpression of the p53-negative regulator MDM2. Epstein-Barr virus (EBV) is present in virtually 100% of BL cases occurring in endemic areas, but in only 10-20% of sporadic cases. In EBV(À) BL cells, reactivation of p53, induced by reducing MDM2 protein level, led to apoptosis. We show here that nutlin-3, a potent antagonist of MDM2, activates the p53 pathway in all BL cell lines harboring wild-type p53, regardless of EBV status. However, nutlin-3 strongly induced apoptosis in EBV(À) or latency I EBV( þ ) cells, whereas latency III EBV( þ ) cells were much more resistant. Prior treatment with sublethal doses of nutlin-3 sensitizes EBV(À) or latency I EBV( þ ) cells to apoptosis induced by etoposide or melphalan, but protects latency III EBV( þ ) cells. p21 WAF1 which is overexpressed in the latter, is involved in this protective effect, as siRNA-mediated inhibition of p21 WAF1 restores sensitivity to etoposide. Nutlin-3 protects latency III BL cells by inducing a p21 WAF1 -mediated G1 arrest. Most BL patients with wild-type p53 tumors could therefore benefit from treatment with nutlin-3, after a careful determination of the latency pattern of EBV in infected patients.

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“…As many as half of all human and murine lymphomas overexpress Mdm2 protein, including lymphomas that have inactivated the tumor suppressor p53 or p14/p19 ARF (Watanabe et al, 1996;Eischen et al, 1999;Alt et al, 2003;Wilda et al, 2004;Ghobrial et al, 2005). Mdm2 is an essential intermediary in the ARFp53 tumor suppressor pathway.…”

Section: Introductionmentioning

confidence: 99%

Elevated Mdm2 expression induces chromosomal instability and confers a survival and growth advantage to B cells

et al. 2007

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Mdm2, a regulator of the p53 tumor suppressor, is frequently overexpressed in lymphomas, including lymphomas that have inactivated p53. However, the biological consequences of Mdm2 overexpression in lymphocytes are not fully resolved. Here, we report that increased expression of Mdm2 in B cells augmented proliferation and reduced susceptibility to p53-dependent apoptosis, which was due to inhibition of p53 and suppression of p21 expression. Notably, developing and mature B cells from Mdm2 transgenic mice had an increased frequency of chromosomal/chromatid breaks and/or aneuploidy. This Mdm2-mediated genome instability occurred at a similar frequency as that in B cells overexpressing the oncogene c-Myc, but the chromosomal instability was not further enhanced when Mdm2 and c-Myc were overexpressed together. Elevated Mdm2 expression alone increased the occurrence of B-cell transformation in vivo and cooperated with c-Myc overexpression, resulting in an acceleration of B-cell lymphomagenesis. In addition, the frequency of p53 mutations was reduced, but not eliminated, in lymphomas arising in Mdm2/Emu-myc double transgenic mice. Therefore, increased Mdm2 expression facilitated B-cell lymphomagenesis, in part, through regulation of p53 by altering B-cell proliferation and susceptibility to apoptosis, and by inducing chromosomal instability

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Inactivation of the ARF–MDM-2–p53 pathway in sporadic Burkitt's lymphoma in children

Cited by 57 publications

References 35 publications

Combined inhibition of PI3K-related DNA damage response kinases and mTORC1 induces apoptosis in MYC-driven B-cell lymphomas

Combined inhibition of PI3K-related DNA damage response kinases and mTORC1 induces apoptosis in MYC-driven B-cell lymphomas

Activation of p53 by MDM2 antagonists has differential apoptotic effects on Epstein–Barr virus (EBV)-positive and EBV-negative Burkitt's lymphoma cells

Elevated Mdm2 expression induces chromosomal instability and confers a survival and growth advantage to B cells

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