Paradoxical Effects of MLL Paralogs in MLL-Rearranged Leukemia

Publication date: 12 June 2017
Source:Cancer Cell, Volume 31, Issue 6
Author(s): Michael J. Thirman
Conflicting data exist on the requirement for wild-type MLL1 in MLL-rearranged leukemia. In this issue of Cancer Cell, Chen et al. describe complementary approaches demonstrating that MLL1 is dispensable for MLL-fusion-mediated leukemogenesis. They also observe an unexpected role for MLL2 in MLL-rearranged leukemia cells and identify potential therapeutic targets.

Teaser

Conflicting data exist on the requirement for wild-type MLL1 in MLL-rearranged leukemia. In this issue of Cancer Cell, Chen et al. describe complementary approaches demonstrating that MLL1 is dispensable for MLL-fusion-mediated leukemogenesis. They also observe an unexpected role for MLL2 in MLL-rearranged leukemia cells and identify potential therapeutic targets.


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Aberrant Glycosylation in Cancer: A Novel Molecular Mechanism Controlling Metastasis

Publication date: 12 June 2017
Source:Cancer Cell, Volume 31, Issue 6
Author(s): Ana Magalhães, Henrique O. Duarte, Celso A. Reis
Glycosylation alterations are involved in several steps of human cancer pathogenesis. In this issue of Cancer Cell, Agrawal et al. identified the glycosyltransferase FUT8 as a previously unrecognized mediator of melanoma metastasis, establishing core fucosylation as a potential therapeutic target for prevention and treatment of metastatic tumors.

Teaser

Glycosylation alterations are involved in several steps of human cancer pathogenesis. In this issue of Cancer Cell, Agrawal et al. identified the glycosyltransferase FUT8 as a previously unrecognized mediator of melanoma metastasis, establishing core fucosylation as a potential therapeutic target for prevention and treatment of metastatic tumors.


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Intertumoral Heterogeneity within Medulloblastoma Subgroups

Publication date: 12 June 2017
Source:Cancer Cell, Volume 31, Issue 6
Author(s): Florence M.G. Cavalli, Marc Remke, Ladislav Rampasek, John Peacock, David J.H. Shih, Betty Luu, Livia Garzia, Jonathon Torchia, Carolina Nor, A. Sorana Morrissy, Sameer Agnihotri, Yuan Yao Thompson, Claudia M. Kuzan-Fischer, Hamza Farooq, Keren Isaev, Craig Daniels, Byung-Kyu Cho, Seung-Ki Kim, Kyu-Chang Wang, Ji Yeoun Lee, Wieslawa A. Grajkowska, Marta Perek-Polnik, Alexandre Vasiljevic, Cecile Faure-Conter, Anne Jouvet, Caterina Giannini, Amulya A. Nageswara Rao, Kay Ka Wai Li, Ho-Keung Ng, Charles G. Eberhart, Ian F. Pollack, Ronald L. Hamilton, G. Yancey Gillespie, James M. Olson, Sarah Leary, William A. Weiss, Boleslaw Lach, Lola B. Chambless, Reid C. Thompson, Michael K. Cooper, Rajeev Vibhakar, Peter Hauser, Marie-Lise C. van Veelen, Johan M. Kros, Pim J. French, Young Shin Ra, Toshihiro Kumabe, Enrique López-Aguilar, Karel Zitterbart, Jaroslav Sterba, Gaetano Finocchiaro, Maura Massimino, Erwin G. Van Meir, Satoru Osuka, Tomoko Shofuda, Almos Klekner, Massimo Zollo, Jeffrey R. Leonard, Joshua B. Rubin, Nada Jabado, Steffen Albrecht, Jaume Mora, Timothy E. Van Meter, Shin Jung, Andrew S. Moore, Andrew R. Hallahan, Jennifer A. Chan, Daniela P.C. Tirapelli, Carlos G. Carlotti, Maryam Fouladi, José Pimentel, Claudia C. Faria, Ali G. Saad, Luca Massimi, Linda M. Liau, Helen Wheeler, Hideo Nakamura, Samer K. Elbabaa, Mario Perezpeña-Diazconti, Fernando Chico Ponce de León, Shenandoah Robinson, Michal Zapotocky, Alvaro Lassaletta, Annie Huang, Cynthia E. Hawkins, Uri Tabori, Eric Bouffet, Ute Bartels, Peter B. Dirks, James T. Rutka, Gary D. Bader, Jüri Reimand, Anna Goldenberg, Vijay Ramaswamy, Michael D. Taylor
While molecular subgrouping has revolutionized medulloblastoma classification, the extent of heterogeneity within subgroups is unknown. Similarity network fusion (SNF) applied to genome-wide DNA methylation and gene expression data across 763 primary samples identifies very homogeneous clusters of patients, supporting the presence of medulloblastoma subtypes. After integration of somatic copy-number alterations, and clinical features specific to each cluster, we identify 12 different subtypes of medulloblastoma. Integrative analysis using SNF further delineates group 3 from group 4 medulloblastoma, which is not as readily apparent through analyses of individual data types. Two clear subtypes of infants with Sonic Hedgehog medulloblastoma with disparate outcomes and biology are identified. Medulloblastoma subtypes identified through integrative clustering have important implications for stratification of future clinical trials.

Graphical abstract

Teaser

Cavalli et al. analyze 763 primary medulloblastoma samples using the similarity network fusion approach. They identify subtypes that have distinct somatic copy-number aberrations, activated pathways, and clinical outcomes within each of the four known subgroups and further delineate group 3 from group 4 MB.


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MLL2, Not MLL1, Plays a Major Role in Sustaining MLL-Rearranged Acute Myeloid Leukemia

Publication date: 12 June 2017
Source:Cancer Cell, Volume 31, Issue 6
Author(s): Yufei Chen, Konstantinos Anastassiadis, Andrea Kranz, A. Francis Stewart, Kathrin Arndt, Claudia Waskow, Akihiko Yokoyama, Kenneth Jones, Tobias Neff, Yoo Lee, Patricia Ernst
The MLL1 histone methyltransferase gene undergoes many distinct chromosomal rearrangements to yield poor-prognosis leukemia. The remaining wild-type allele is most commonly, but not always, retained. To what extent the wild-type allele contributes to leukemogenesis is unclear. Here we show, using rigorous, independent animal models, that endogenous MLL1 is dispensable for MLL-rearranged leukemia. Potential redundancy was addressed by co-deleting the closest paralog, Mll2. Surprisingly, Mll2 deletion alone had a significant impact on survival of MLL-AF9-transformed cells, and additional Mll1 loss further reduced viability and proliferation. We show that MLL1/MLL2 collaboration is not through redundancy, but regulation of distinct pathways. These findings highlight the relevance of MLL2 as a drug target in MLL-rearranged leukemia and suggest its broader significance in AML.

Graphical abstract

Teaser

Chen et al. report that wild-type MLL1 is dispensable for MLL fusion leukemia, but instead loss of MLL2 reduces the survival of leukemia cells from human cell lines and in a mouse model of MLL-AF9 AML. Combined loss of MLL1 and MLL2 further reduces leukemia cell viability.


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From One to Many: Further Refinement of Medulloblastoma Subtypes Offers Promise for Personalized Therapy

Publication date: 12 June 2017
Source:Cancer Cell, Volume 31, Issue 6
Author(s): Abhishek Bavle, D. Williams Parsons
There is significant intertumoral heterogeneity within the four molecular subgroups of medulloblastoma. In this issue of Cancer Cell, Cavalli et al. apply similarity network fusion to gene expression and DNA methylation data to identify 12 medulloblastoma subtypes with distinct molecular and clinical profiles, making an important step toward molecularly tailored therapy.

Teaser

There is significant intertumoral heterogeneity within the four molecular subgroups of medulloblastoma. In this issue of Cancer Cell, Cavalli et al. apply similarity network fusion to gene expression and DNA methylation data to identify 12 medulloblastoma subtypes with distinct molecular and clinical profiles, making an important step toward molecularly tailored therapy.


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Kupffer Cell-Derived Tnf Triggers Cholangiocellular Tumorigenesis through JNK due to Chronic Mitochondrial Dysfunction and ROS

Publication date: 12 June 2017
Source:Cancer Cell, Volume 31, Issue 6
Author(s): Detian Yuan, Shan Huang, Emanuel Berger, Lei Liu, Nina Gross, Florian Heinzmann, Marc Ringelhan, Tracy O. Connor, Mira Stadler, Michael Meister, Julia Weber, Rupert Öllinger, Nicole Simonavicius, Florian Reisinger, Daniel Hartmann, Rüdiger Meyer, Maria Reich, Marco Seehawer, Valentina Leone, Bastian Höchst, Dirk Wohlleber, Simone Jörs, Marco Prinz, Duncan Spalding, Ulrike Protzer, Tom Luedde, Luigi Terracciano, Matthias Matter, Thomas Longerich, Percy Knolle, Thomas Ried, Verena Keitel, Fabian Geisler, Kristian Unger, Einat Cinnamon, Eli Pikarsky, Norbert Hüser, Roger J. Davis, Darjus F. Tschaharganeh, Roland Rad, Achim Weber, Lars Zender, Dirk Haller, Mathias Heikenwalder
Intrahepatic cholangiocarcinoma (ICC) is a highly malignant, heterogeneous cancer with poor treatment options. We found that mitochondrial dysfunction and oxidative stress trigger a niche favoring cholangiocellular overgrowth and tumorigenesis. Liver damage, reactive oxygen species (ROS) and paracrine tumor necrosis factor (Tnf) from Kupffer cells caused JNK-mediated cholangiocellular proliferation and oncogenic transformation. Anti-oxidant treatment, Kupffer cell depletion, Tnfr1 deletion, or JNK inhibition reduced cholangiocellular pre-neoplastic lesions. Liver-specific JNK1/2 deletion led to tumor reduction and enhanced survival in Akt/Notch- or p53/Kras-induced ICC models. In human ICC, high Tnf expression near ICC lesions, cholangiocellular JNK-phosphorylation, and ROS accumulation in surrounding hepatocytes are present. Thus, Kupffer cell-derived Tnf favors cholangiocellular proliferation/differentiation and carcinogenesis. Targeting the ROS/Tnf/JNK axis may provide opportunities for ICC therapy.

Graphical abstract

Teaser

Yuan et al. show that mitochondrial dysfunction and oxidative stress in the liver increase tumor necrosis factor (TNF) expression by Kupffer cells to cause JNK-mediated cholangiocellular proliferation and transformation. The ROS/TNF/JNK axis may be an effective target for intrahepatic cholangiocarcinoma therapy.


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ACK1/TNK2 Regulates Histone H4 Tyr88-phosphorylation and AR Gene Expression in Castration-Resistant Prostate Cancer

Publication date: 12 June 2017
Source:Cancer Cell, Volume 31, Issue 6
Author(s): Kiran Mahajan, Pavani Malla, Harshani R. Lawrence, Zhihua Chen, Chandan Kumar-Sinha, Rohit Malik, Sudhanshu Shukla, Jongphil Kim, Domenico Coppola, Nicholas J. Lawrence, Nupam P. Mahajan
The androgen receptor (AR) is critical for the progression of prostate cancer to a castration-resistant (CRPC) state. AR antagonists are ineffective due to their inability to repress the expression of AR or its splice variant, AR-V7. Here, we report that the tyrosine kinase ACK1 (TNK2) phosphorylates histone H4 at tyrosine 88 upstream of the AR transcription start site. The WDR5/MLL2 complex reads the H4-Y88-phosphorylation marks and deposits the transcriptionally activating H3K4-trimethyl marks promoting AR transcription. Reversal of the pY88-H4 epigenetic marks by the ACK1 inhibitor (R)-9bMS-sensitized naive and enzalutamide-resistant prostate cancer cells and reduced AR and AR-V7 levels to mitigate CRPC tumor growth. Thus, a feedforward ACK1/pY88-H4/WDR5/MLL2/AR epigenetic circuit drives CRPC and is necessary for maintenance of the malignant state.

Graphical abstract

Teaser

Mahajan et al. report that ACK1 phosphorylates histone H4 at Y88 upstream of the AR transcription start site, leading to the WDR5/MLL2 complex-mediated increase of AR transcription. Inhibition of ACK1 reverses the pY88-H4 marks and reduces AR and AR-V7 levels to mitigate castration-resistant prostate tumor growth.


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