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000143394 0247_ $$2ISSN$$a0099-7013
000143394 0247_ $$2ISSN$$a0099-7374
000143394 0247_ $$2ISSN$$a1538-7445
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000143394 037__ $$aDKFZ-2019-00982
000143394 041__ $$aeng
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000143394 1001_ $$aTao, Ran$$b0
000143394 245__ $$aMYC drives Group 3 medulloblastoma through transformation of Sox2+ astrocyte progenitor cells.
000143394 260__ $$aPhiladelphia, Pa.$$bAACR$$c2019
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000143394 520__ $$aA subset of Group 3 medulloblastoma frequently harbors amplification or overexpression of MYC lacking additional focal aberrations, yet it remains unclear whether MYC overexpression alone can induce tumorigenesis and which cells give rise to these tumors. Here, we showed that astrocyte progenitors in the early postnatal cerebellum were susceptible to transformation by MYC. The resulting tumors specifically resembled human Group 3 medulloblastoma based on histology and gene expression profiling. Gene expression analysis of MYC-driven medulloblastoma cells revealed altered glucose metabolic pathways with marked overexpression of lactate dehydrogenase A (LDHA). LDHA abundance correlated positively with MYC expression and was associated with poor prognosis in human Group 3 medulloblastoma. Inhibition of LDHA significantly reduced growth of both mouse and human MYC-driven tumors but had little effect on normal cerebellar cells or SHH-associated medulloblastoma. By generating a new mouse model, we demonstrated for the first time that astrocyte progenitors can be transformed by MYC and serve as the cells of origin for Group 3 medulloblastoma. Moreover, we identified LDHA as a novel, specific therapeutic target for this devastating disease.
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000143394 7001_ $$aMurad, Najiba$$b1
000143394 7001_ $$aXu, Zhenhua$$b2
000143394 7001_ $$aZhang, Peng$$b3
000143394 7001_ $$0P:(DE-He78)34b3639de467b2c700920d7cbc3d2110$$aOkonechnikov, Konstantin$$b4$$udkfz
000143394 7001_ $$0P:(DE-He78)4c28e2aade5f44d8eca9dd8e97638ec8$$aKool, Marcel$$b5$$udkfz
000143394 7001_ $$aRivero-Hinojosa, Samuel$$b6
000143394 7001_ $$aLazarski, Christopher$$b7
000143394 7001_ $$00000-0003-2598-3544$$aZheng, Pan$$b8
000143394 7001_ $$aLiu, Yang$$b9
000143394 7001_ $$aEberhart, Charles G$$b10
000143394 7001_ $$00000-0003-3221-9421$$aRood, Brian R$$b11
000143394 7001_ $$aPacker, Roger$$b12
000143394 7001_ $$aPei, Yanxin$$b13
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000143394 9141_ $$y2019
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