BMI1 in medulloblastoma [Neurosurgery Wiki]

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====== BMI1 in medulloblastoma ======

The molecular dissection of the [[CHD7]]-[[BMI1]]-[[MAPK]] regulatory axis in BMI1 High; [[CHD7]] Low [[medulloblastoma]] identifies this signature as a proxy to predict MAPK functional activation, which can be effectively drugged in preclinical models, and paves the way for further exploration of combined BMI1 and MAPK targeting in [[Group 4 medulloblastoma]] patients
((Badodi S, Pomella N, Lim YM, Brandner S, Morrison G, Pollard SM, Zhang X, Zabet NR, Marino S. Combination of [[BMI1]] and [[MAPK]]/[[ERK]] inhibitors is effective in [[medulloblastoma]]. Neuro Oncol. 2022 Feb 25:noac052. doi: 10.1093/neuonc/noac052. Epub ahead of print. PMID: 35213723.)).
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Badodi et al. identified a BMI1-dependent sensitivity to deregulation of inositol metabolism in a proportion of medulloblastoma. We demonstrate mTOR pathway activation and metabolic adaptation specifically in medulloblastoma of the molecular subgroup G4 characterized by a BMI1High; CHD7Low signature and show this can be counteracted by IP6 treatment. Finally, we demonstrate that IP6 synergizes with cisplatin to enhance its cytotoxicity in vitro and extends survival in a pre-clinical BMI1High; CHD7Low xenograft model
((Badodi S, Pomella N, Zhang X, Rosser G, Whittingham J, Niklison-Chirou MV, Lim YM, Brandner S, Morrison G, Pollard SM, Bennett CD, Clifford SC, Peet A, Basson MA, Marino S. Inositol treatment inhibits medulloblastoma through suppression of epigenetic-driven metabolic adaptation. Nat Commun. 2021 Apr 12;12(1):2148. doi: 10.1038/s41467-021-22379-7. PMID: 33846320; PMCID: PMC8042111.)).
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Analyses of tumor samples from patients with MB showed that the stemness markers BMI1 and CD133 are expressed in all molecular subgroups of MB. The HDAC inhibitor (HDACi) NaB reduced cell viability and expression of BMI1 and CD133 and increased acetylation in human MB cells. Enrichment analysis of genes associated with CD133 or BMI1 expression showed mitogen-activated protein kinase (MAPK)/ERK signaling as the most enriched processes in MB tumor
((da Cunha Jaeger M, Ghisleni EC, Cardoso PS, Siniglaglia M, Falcon T, Brunetto AT, Brunetto AL, de Farias CB, Taylor MD, Nör C, Ramaswamy V, Roesler R. HDAC and MAPK/ERK Inhibitors Cooperate To Reduce Viability and Stemness in Medulloblastoma. J Mol Neurosci. 2020 Jun;70(6):981-992. doi: 10.1007/s12031-020-01505-y. Epub 2020 Feb 13. PMID: 32056089.)).
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Bakhshinyan describes the [[epigenetic regulator]] BMI1 as a novel therapeutic target for the treatment of recurrent human Group 3 MB, a childhood brain tumor for which there is virtually no treatment option beyond palliation. Current clinical trials for recurrent MB patients based on genomic profiles of primary, treatment-naive tumors will provide limited clinical benefit since recurrent metastatic MBs are highly genetically divergent from their primary tumor. Using a small molecule inhibitor against BMI1
((Bakhshinyan D, Venugopal C, Adile AA, Garg N, Manoranjan B, Hallett R, Wang X, Mahendram S, Vora P, Vijayakumar T, Subapanditha M, Singh M, Kameda-Smith MM, Qazi M, McFarlane N, Mann A, Ajani OA, Yarascavitch B, Ramaswamy V, Farooq H, Morrissy S, Cao L, Sydorenko N, Baiazitov R, Du W, Sheedy J, Weetall M, Moon YC, Lee CS, Kwiecien JM, Delaney KH, Doble B, Cho YJ, Mitra S, Kaplan D, Taylor MD, Davis TW, Singh SK. BMI1 is a therapeutic target in recurrent medulloblastoma. Oncogene. 2019 Mar;38(10):1702-1716. doi: 10.1038/s41388-018-0549-9. Epub 2018 Oct 22. PMID: 30348991.)).
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Kahn et al. identified a mechanism in which [[NOTCH1]] activates BMI1 through the activation of [[TWIST1]]. NOTCH1 expression and activity are directly related to medulloblastoma metastasis and decreased survival rate of tumor-bearing mice
((Kahn SA, Wang X, Nitta RT, Gholamin S, Theruvath J, Hutter G, Azad TD, Wadi L, Bolin S, Ramaswamy V, Esparza R, Liu KW, Edwards M, Swartling FJ, Sahoo D, Li G, Wechsler-Reya RJ, Reimand J, Cho YJ, Taylor MD, Weissman IL, Mitra SS, Cheshier SH. Notch1 regulates the initiation of metastasis and self-renewal of Group 3 medulloblastoma. Nat Commun. 2018 Oct 8;9(1):4121. doi: 10.1038/s41467-018-06564-9. Erratum in: Nat Commun. 2018 Nov 2;9(1):4651. PMID: 30297829; PMCID: PMC6175869.)).
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Badodi et al. described molecular convergence between [[BMI1]] and [[CHD7]] in the initiation of [[medulloblastoma]]. Identified in a functional genomic screen in [[mouse]] models, a BMI1High;CHD7Low expression signature within medulloblastoma characterizes patients with poor [[overall survival]]. 

They showed that BMI1-mediated repression of the [[ERK1]]/2 pathway leads to increased proliferation and tumor burden in primary human MB cells and in a [[xenograft]] model, respectively. They provided evidence that repression of the ERK inhibitor [[DUSP4]] by BMI1 is dependent on a more accessible [[chromatin]] configuration in G4 MB cells with low CHD7 expression. These findings extend current knowledge of the role of BMI1 and CHD7 in medulloblastoma pathogenesis, and they raise the possibility that pharmacological targeting of BMI1 or ERK may be particularly indicated in a subgroup of MB with low expression levels of CHD7
((Badodi S, Dubuc A, Zhang X, Rosser G, Da Cunha Jaeger M, Kameda-Smith MM,
Morrissy AS, Guilhamon P, Suetterlin P, Li XN, Guglielmi L, Merve A, Farooq H,
Lupien M, Singh SK, Basson MA, Taylor MD, Marino S. Convergence of BMI1 and CHD7 
on ERK Signaling in Medulloblastoma. Cell Rep. 2017 Dec 5;21(10):2772-2784. doi: 
10.1016/j.celrep.2017.11.021. PubMed PMID: 29212025; PubMed Central PMCID:
PMC5732319.
)).
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Repression of the [[ERK]] inhibitor [[DUSP4]] by BMI1 is dependent on a more accessible chromatin configuration in G4 MB cells with low [[CHD7]] expression. These findings extend current knowledge of the role of BMI1 and CHD7 in [[medulloblastoma pathogenesis]], and they raise the possibility that pharmacological targeting of BMI1 or ERK may be particularly indicated in a subgroup of MB with low expression levels of CHD7
((Badodi S, Dubuc A, Zhang X, Rosser G, Da Cunha Jaeger M, Kameda-Smith MM, Morrissy AS, Guilhamon P, Suetterlin P, Li XN, Guglielmi L, Merve A, Farooq H, Lupien M, Singh SK, Basson MA, Taylor MD, Marino S. Convergence of BMI1 and CHD7 on ERK Signaling in Medulloblastoma. Cell Rep. 2017 Dec 5;21(10):2772-2784. doi: 10.1016/j.celrep.2017.11.021. PMID: 29212025; PMCID: PMC5732319.)).