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. 2015 Jan 12;27(1):72–84. doi: 10.1016/j.ccell.2014.11.002

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© 2015 The Authors

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).

PMC Copyright notice

Aberrant Expression of MYCN in Combination with p53 Loss of Function Drives Highly Penetrant and Aggressive Medulloblastoma

(A) Kaplan-Meier survival curves for GTML/Trp53^KI/KI (n = 43), GTML/Trp53^KI/WT (n = 83), or GTML transgenic mice (n = 50) mice as indicated. p, log rank test.

(B) H&E and immunohistochemical staining indicating levels of MYCN protein and cell proliferation (Ki-67) in GTML/Trp53^KI/KI and GTML transgenic mice.

(C) Subgroup classification of mouse expression profiles using a support vector machine trained on human medulloblastoma expression profiles and nonnegative matrix factorization for cross-species projection.

(D) Kaplan-Meier survival for GTML/Trp53^KI/KI mice treated with doxycycline (Dox, n = 8) or tamoxifen (Tam, n = 10) compared to vehicle (n = 9) as indicated. p, log rank test.

(E) GTML/Trp53^KI/KI mice coexpressing firefly luciferase (FLuc) were treated with Tam, Dox, or vehicle for 9 days. Bioluminescent imaging of GTML/Trp53^KI/KI mice after 9 days treatment with Dox or Tam as indicated (top). Luminescence intensity at days 0 and 9 are shown (bottom). Data points represent individual mice. p, unpaired t test.

(F) H&E and immunohistochemical staining indicating levels of MYCN, Ki-67, or apoptosis (cleaved caspase 3) in GTML/Trp53^KI/KI mice after treatment with Dox or Tam.

(G) RNAscope 2-plex chromogenic assay. Cdkn1a expression (red) was analyzed on brain sections from GTML/Trp53^KI/KI mice treated with either Tam or vehicle control as indicated. Samples were costained for expression of the Ubc (ubiquitin C) housekeeping gene (green). Expression of Ppib (Peptidylprolyl Isomerase B, Cyclophilin B) (red) and Polr2a (DNA-directed RNA polymerase II subunit RPB1) (green) were used as positive controls. Expression of dapB (dihydrodipicolinate) reductase gene from B. subtilis was used as a negative control. Sections were counterstained with Gill’s hematoxylin.

(H) Fold difference of human MYCN or mouse Cdkn1a mRNA levels in tumor tissues treated with either Dox or Tam. (p, unpaired t test.)

Scale bars, 50 μm. Error bars represent mean ± SD. See also Figure S3 and Table S5.