Article
Hematology
Elif Karaca Atabay, Carmen Mecca, Qi Wang, Chiara Ambrogio, Ines Mota, Nina Prokoph, Giulia Mura, Cinzia Martinengo, Enrico Patrucco, Giulia Leonardi, Jessica Hossa, Achille Pich, Luca Mologni, Carlo Gambacorti-Passerini, Laurence Brugieres, Birgit Geoerger, Suzanne D. Turner, Claudia Voena, Taek-Chin Cheong, Roberto Chiarle
Summary: This study identified PTPN1 and PTPN2 phosphatases as drivers of resistance to ALK TKIs in ALK(+) ALCL. These phosphatases regulate ALK phosphorylation and activity, and their loss leads to TKI resistance. Furthermore, SHP2 is a key mediator of oncogenic ALK signaling, and PTPN1 acts as a phosphatase for SHP2. Combination therapy with a SHP2 inhibitor can overcome TKI resistance in ALK(+) ALCL.
Article
Oncology
Dimitrios Chioureas, Janina Beck, George Baltatzis, Ioulia Vardaki, Pedro Fonseca, Nikolaos Tsesmetzis, Francisco Vega, Vasiliki Leventaki, Aristides G. Eliopoulos, Elias Drakos, George Z. Rassidakis, Theocharis Panaretakis
Summary: ALK+ anaplastic large cell lymphoma (ALK+ ALCL) is an aggressive non-Hodgkin lymphoma characterized by overexpression and activation of ALK kinase due to chromosomal translocations. This study demonstrates that ALK+ ALCL cells secrete exosomes containing critical components of ALK signaling which can be taken up by other cells, influencing tumor microenvironment and possibly contributing to treatment resistance. The interactions between ALK signaling and the microenvironment in ALK+ ALCL are not fully understood, but this research shows that exosome-mediated activation of stromal cells can alter the cytokine profile of the microenvironment, potentially impacting tumor aggressiveness and resistance to treatment.
Article
Hematology
Zhenguo Zi, Shujuan Du, Liming Zhang, Yuebo Wang, Ling Ding, Chongqi Zhang, Huanyu Wang, Jan Pawlicki, Yuan Cai, Yazhou Yao, Feng Zhou, Yin Tong, James L. Riley, Qiliang Cai, Xiaojing Ma, Fang Wei
Summary: GOLM1 is significantly upregulated in ALK-positive anaplastic large cell lymphoma (ALCL) and plays a critical role in promoting cell growth and viability. It directly interacts with B-cell lymphoma-extra large protein, prolongs its stability, and suppresses apoptosis. GOLM1 may serve as a potential biomarker and therapeutic target in ALK-induced hematological malignancies.
Article
Oncology
Gavin D. Garland, Stephen P. Ducray, Leila Jahangiri, Perla Pucci, G. A. Amos Burke, Jack Monahan, Raymond Lai, Olaf Merkel, Ana-Iris Schiefer, Lukas Kenner, Andrew J. Bannister, Suzanne D. Turner
Summary: Research has shown that nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) drives anaplastic large cell lymphoma (ALCL) by regulating another protein, BRG1, to promote tumor cell proliferation. Inactivation of the gene that leads to expression of BRG1 results in tumor cell death, suggesting that therapeutic targeting of BRG1 may be a novel therapy for this form of cancer.
Article
Oncology
Eric J. Lowe, Anne F. Reilly, Megan S. Lim, Thomas G. Gross, Lauren Saguilig, Donald A. Barkauskas, Rui Wu, Sarah Alexander, Catherine M. Bollard
Summary: The ANHL12P1 clinical trial demonstrated that the addition of CZ to standard treatment prevented relapses during therapy for children with nonlocalized ALK+ CD30+ ALCL, MDD predicted EFS, and the addition of CZ resulted in unexpected thromboembolic events.
JOURNAL OF CLINICAL ONCOLOGY
(2023)
Article
Cell Biology
Adriana Petrazzuolo, Maria Perez-Lanzon, Isabelle Martins, Peng Liu, Oliver Kepp, Veronique Minard-Colin, Maria Chiara Maiuri, Guido Kroemer
Summary: Immunogenic cell death (ICD) increases the immunogenicity of dying cells through a series of changes, and specific ALK inhibition may induce ICD in ALCL, stimulating the immune system and prolonging survival in cancer patients.
CELL DEATH & DISEASE
(2021)
Review
Pharmacology & Pharmacy
Annette K. Brenner, Maria W. Gunnes
Summary: Neuroblastoma is a malignant tumor that mostly affects young children and is highly heterogeneous, with risk factors including abnormalities in the ALK gene leading to tumorigenesis. Combination therapy with ALK inhibitors may be an effective strategy to reduce drug resistance and improve treatment outcomes.
Article
Oncology
Giulia Mura, Elif Karaca Atabay, Matteo Menotti, Cinzia Martinengo, Chiara Ambrogio, Gloria Giacomello, Maddalena Arigoni, Martina Olivero, Raffaele A. Calogero, Roberto Chiarle, Claudia Voena
Summary: Anaplastic Large Cell Lymphoma (ALCL) is driven by the chimeric tyrosine kinase NPM-ALK, which downregulates the expression of CD45 via STAT3 and acts as a rheostat of ALK oncogenic signaling and resistance to TKI treatment. CD45 is a key regulator of T cell activation and cytokine responses through the JAK/STAT pathway. In ALK+ ALCL, NPM-ALK inhibits T cell molecules expression and activates surrogate TCR signaling. Inhibition of NPM-ALK kinase activity leads to increased expression of CD45RO isoform. Knocking-out CD45 results in increased resistance to ALK TKI treatment.
FRONTIERS IN ONCOLOGY
(2023)
Article
Multidisciplinary Sciences
Huan-Chang Liang, Mariantonia Costanza, Nicole Prutsch, Mark W. Zimmerman, Elisabeth Gurnhofer, Ivonne A. Montes-Mojarro, Brian J. Abraham, Nina Prokoph, Stefan Stoiber, Simone Tangermann, Cosimo Lobello, Jan Oppelt, Ioannis Anagnostopoulos, Thomas Hielscher, Shahid Pervez, Wolfram Klapper, Francesca Zammarchi, Daniel-Adriano Silva, K. Christopher Garcia, David Baker, Martin Janz, Nikolai Schleussner, Falko Fend, Sarka Pospisilova, Andrea Janikova, Jacqueline Wallwitz, Dagmar Stoiber, Ingrid Simonitsch-Klupp, Lorenzo Cerroni, Stefano Pileri, Laurence de Leval, David Sibon, Virginie Fataccioli, Philippe Gaulard, Chalid Assaf, Fabian Knorr, Christine Damm-Welk, Wilhelm Woessmann, Suzanne D. Turner, A. Thomas Look, Stephan Mathas, Lukas Kenner, Olaf Merkel
Summary: The study highlights the importance of the BATF3/IL-2R module in ALCL biology and identifies IL-2R alpha targeting as a promising treatment strategy for ALCL.
NATURE COMMUNICATIONS
(2021)
Article
Chemistry, Medicinal
Shaowen Xie, Yuan Sun, Yulin Liu, Xinnan Li, Xinuo Li, Wenyi Zhong, Feiyan Zhan, Jingjie Zhu, Hong Yao, Dong-Hua Yang, Zhe-Sheng Chen, Jinyi Xu, Shengtao Xu
Summary: Novel ALK degraders based on PROTAC technology showed high specificity in ALK-positive cell lines and significant anti-tumor effects in a mouse model, indicating potential benefits for treating ALK-driven malignancies.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Oncology
V. Subbiahy, S. Kuraviy, S. Ganguly, D. R. Welch, C. J. Vivian, M. U. Mushtaq, A. Hegde, S. Iyer, A. Behrang, S. M. Ali, R. W. Madison, J. M. Venstrom, R. A. Jensen, J. P. McGuirk, H. M. Amin, R. Balusu
Summary: The study demonstrates that Ceritinib shows inhibitory effects on the fusion kinase NPM1-ALK and induces apoptosis of lymphoma cells in vitro and in vivo. Treatment with Ceritinib in the NPM1-ALKthorn ALCL xenograft model resulted in tumor regression and improved survival. Among 19,272 patients sequenced, 0.30% harbored ALK fusions, including various hematologic malignancies.
Review
Medicine, General & Internal
Kuan-Li Wu, Hsiao-Ling Chen, Ying-Ming Tsai, Tai-Huang Lee, Hsiu-Mei Chang, Yu-Chen Tsai, Cheng-Hao Chuang, Yong-Chieh Chang, Yu-Kang Tu, Chih-Jen Yang, Jen-Yu Hung, Inn-Wen Chong
Summary: This study compared newer generation ALKIs for treatment efficacy in Asian groups using network meta-analysis. Results showed that ensartinib may currently be the most effective first-line treatment for Asian patients with ALK-positive NSCLC. Additionally, low-dose alectinib exhibited efficacy similar to a higher dose regimen in Asian populations.
JOURNAL OF CLINICAL MEDICINE
(2021)
Article
Biochemistry & Molecular Biology
Farzaneh Aboualizadeh, Zhong Yao, Jikui Guan, Luka Drecun, Shivanthy Pathmanathan, Jamie Snider, Ganesh Umapathy, Max Kotlyar, Igor Jurisica, Ruth Palmer, Igor Stagljar
Summary: This study systematically characterized the phospho-dependent ALK interactome using the MaMTH system, identifying 30 novel ALK interactors from a library of 86 SH2 domain-containing full length proteins. The interactions of these novel proteins are correlated to ALK phosphorylation activity and NCK2 was further validated as a key interactor in neuroblastoma cells. The study provides a valuable resource list of potential novel ALK signaling components for further exploration.
JOURNAL OF MOLECULAR BIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
I. Garces de los Fayos Alonso, L. Zujo, I Wiest, P. Kodajova, G. Timelthaler, S. Edtmayer, M. Zrimsek, S. Kollmann, C. Giordano, M. Kothmayer, H. A. Neubauer, S. Dey, M. Schlederer, B. S. Schmalzbauer, T. Limberger, C. Probst, O. Pusch, S. Hogler, S. Tangermann, O. Merkel, A. Schiefer, C. Kornauth, N. Prutsch, M. Zimmerman, B. Abraham, J. Anagnostopoulos, L. Quintanilla-Martinez, S. Mathas, P. Wolf, D. Stoiber, P. B. Staber, G. Egger, W. Klapper, W. Woessmann, T. A. Look, P. Gunning, S. D. Turner, R. Moriggl, S. Lagger, L. Kenner
Summary: This study reveals the important role of PDGFRβ in aggressive ALCL and its activation of STAT5 in inducing cell growth and survival-related gene expression. Simultaneous deletion of STAT5 gene products significantly impairs cell viability. Additionally, blockade of PDGFRβ and STAT3/5 activity effectively obstructs tumor development. Thus, PDGFRβ and PDGFRβ-STAT3/5 signaling may serve as novel targets for the treatment of aggressive ALCL.
Article
Biochemistry & Molecular Biology
Mitsuteru Hiwatari, Masafumi Seki, Ryosuke Matsuno, Kenichi Yoshida, Takeshi Nagasawa, Aiko Sato-Otsubo, Shohei Yamamoto, Motohiro Kato, Kentaro Watanabe, Masahiro Sekiguchi, Satoru Miyano, Seishi Ogawa, Junko Takita
Summary: A fusion gene composed of portions of the TENM3 gene and the ALK gene has been identified in tumor cells from patients with neuroblastoma. The fusion gene leads to the formation of a fusion protein with constitutive tyrosine kinase activity, which may serve as a therapeutic target and diagnostic molecular marker for neuroblastoma.
Article
Psychiatry
Rohit J. Lodhi, Salaj Masand, Amna Malik, Kuppuswami Shivakumar, Victoria D. M. McAllister, Veronica O'Keane, Leah C. Young, Adrian H. Heald, Roy A. Sherwood, Katherine J. Aitchison
SCHIZOPHRENIA RESEARCH
(2016)
Article
Pathology
Fang Wu, Peng Wang, Leah C. Young, Raymond Lai, Liang Li
AMERICAN JOURNAL OF PATHOLOGY
(2009)
Article
Pathology
Leah C. Young, Kathleen M. Bone, Peng Wang, Fang Wu, Benjamin A. Adam, Samar Hegazy, Pascal Gelebart, Jelena Holovati, Liang Li, Susan E. Andrew, Raymond Lai
AMERICAN JOURNAL OF PATHOLOGY
(2011)
Review
Biochemistry & Molecular Biology
Leah C. Young, Michael J. Hendzel
BIOCHEMISTRY AND CELL BIOLOGY
(2013)
Article
Hematology
Ping Shi, Raymond Lai, Quan Lin, Abid S. Iqbal, Leah C. Young, Larry W. Kwak, Richard J. Ford, Hesham M. Amin
Article
Oncology
Peng Wang, Fang Wu, Jingdong Zhang, Todd McMullen, Leah C. Young, Robert J. Ingham, Liang Li, Raymond Lai
Article
Cell Biology
Stuart Campbell, Ismail Hassan Ismail, Leah C. Young, Guy G. Poirier, Michael J. Hendzel
Article
Genetics & Heredity
Kelly A. D. Narine, Angela M. Keuling, Randi Gombos, Victor A. Tron, Susan E. Andrew, Leah C. Young
Article
Biochemistry & Molecular Biology
Frederick A. Mallette, Francesca Mattiroli, Gaofeng Cui, Leah C. Young, Michael J. Hendzel, Georges Mer, Titia K. Sixma, Stephane Richard
Article
Biochemistry & Molecular Biology
J. Dien Bard, P. Gelebart, H. M. Amin, L. C. Young, Y. Ma, R. Lai
Article
Biochemistry & Molecular Biology
Leah C. Young, Darin W. McDonald, Michael J. Hendzel
JOURNAL OF BIOLOGICAL CHEMISTRY
(2013)
Article
Biochemical Research Methods
Fang Wu, Peng Wang, Jingdong Zhang, Leah C. Young, Raymond Lai, Liang Li
MOLECULAR & CELLULAR PROTEOMICS
(2010)
Meeting Abstract
Hematology
Anthea C. Peters, Randy Chung, Charles S. Wong, Leah C. Young, Tony Reiman, Raymond Lai
Meeting Abstract
Psychiatry
S. Masand, R. Sherwood, K. J. Aitchison
EUROPEAN PSYCHIATRY
(2011)