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A registry of patients and families funded through the International Waldenstrom’s Macroglobulinemia Foundation has recruited over 1000 patients and family members to study the genetic basis and predispositions for WM. The use of whole genome sequencing (WGS) has been used by us to define the genomic landscape of WM. Using paired normal/tumor tumor samples, we identified and validated highly recurring MYD88 (L265P) and CXCR4 WHIM-like somatic mutations. The discovery of MYD88 L265P somatic mutation which is present in 95% of WM patients has permitted the differentiation of WM from overlapping B-cell disorders, including marginal zone lymphoma and IgM myeloma. The feasibility for the diagnostic and response assessment potential for MYD88 L265P peripheral blood testing in WM was also demonstrated by my laboratory. In as well, my laboratory has worked on MYD88 L265P signaling in WM including and has shown the activation of IRAK 1/4/TRAF6/NFKB and defined for the first time signaling through Bruton’s tyrosine kinase (BTK). These findings led to a clinical trial in WM patients using the BTK inhibitor ibrutinib which has shown remarkable activity in relapsed/refractory WM patients, and led to the first breakthrough designation in oncology by the U.S. FDA, and subsequent approval of ibrutinib by the FDA and EMA for the treatment of WM. Our current efforts are now focused on defining the role of other recurring mutations in WM that are observed at lower frequencies, but which may still have important impact on pathogenesis and treatment (e.g. ARID1A, CD79A/B, and TP53),
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Yu-Tzu Tai, Gerrard Teoh,Boris Lin,Faith E Davies,Dharminder Chauhan,Steven P Treon,Noopur Raje,Teru Hideshima, Yoshihito Shima,Klaus Podar,Kenneth C Anderson
Journal of immunology (Baltimore, Md. : 1950) (2024)
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NATURE MEDICINE (2024)
Yu-Tzu Tai, Laurence P Catley,Constantine S Mitsiades,Renate Burger,Klaus Podar, Reshma Shringpaure,Teru Hideshima,Dharminder Chauhan, Makoto Hamasaki,Kenji Ishitsuka,Paul Richardson,Steven P Treon,
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Blood (2023): 213
Jorge Castillo,Shayna Sarosiek,Andrew Branagan, Alex Bokun, Hillary Peltier, Vincent Girardi, Michelle Pacia,Steven Treon
CLINICAL LYMPHOMA MYELOMA & LEUKEMIA (2023): S273-S274
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Jorge J. Castillo,Shayna R Sarosiek,Andrew R. Branagan,Catherine A. Flynn,Megan Little, Katherine Stockman,Timothy P. White, Alexandra N. Eurell,Maria Luisa Guerrera,Amanda Kofides,Shirong Liu,Xia Liu,
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Jorge J. Castillo,Andrew R. Branagan, David Sermer,Catherine A. Flynn,Kirsten Meid,Megan Little, Katherine Stockman,Timothy White, Alexa Canning,Maria L. Guerrera,Amanda Kofides,Shirong Liu,
Bloodno. 7 (2023): 582-591
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