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1. Thrombosis risk in single- and double-heterozygous carriers of factor V Leiden and prothrombin G20210A in FinnGen and the UK Biobank

Author

Palotie, Aarno, Daly, Mark, Riley-Gills, Bridget, Jacob, Howard, Viollet, Coralie, Petrovski, Slavé, Chen, Chia-Yen, John, Sally, Okafo, George, Plenge, Robert, Maranville, Joseph, McCarthy, Mark, Pendergrass, Rion, Ehm, Margaret G., Auro, Kirsi, Longerich, Simonne, Mälarstig, Anders, Vlahiotis, Anna, Klinger, Katherine, Chatelain, Clement, Gossel, Matthias, Estrada, Karol, Graham, Robert, Waterworth, Dawn, O´Donnell, Chris, Renaud, Nicole, Mäkelä, Tomi P., Kaprio, Jaakko, Ruddock, Minna, Virolainen, Petri, Hakanen, Antti, Kilpi, Terhi, Perola, Markus, Partanen, Jukka, Raivio, Taneli, Tikkanen, Jani, Serpi, Raisa, Kristiansson, Kati, Kosma, Veli-Matti, Laukkanen, Jari, Hautalahti, Marco, Tuovila, Outi, Waring, Jeffrey, Riley-Gillis, Bridget, Rahimov, Fedik, Tachmazidou, Ioanna, Ding, Zhihao, Jung, Marc, Tuoken, Hanati, Biswas, Shameek, Pulford, David, Raghavan, Neha, Huertas-Vazquez, Adriana, Sul, Jae-Hoon, Hu, Xinli, Hedman, Åsa, Obeidat, Ma´en, Chung, Jonathan, Zierer, Jonas, Niemi, Mari, Ripatti, Samuli, Schleutker, Johanna, Arvas, Mikko, Carpén, Olli, Hinttala, Reetta, Kettunen, Johannes, Mannermaa, Arto, Aalto-Setälä, Katriina, Kähönen, Mika, Mäkelä, Johanna, Kälviäinen, Reetta, Julkunen, Valtteri, Soininen, Hilkka, Remes, Anne, Hiltunen, Mikko, Peltola, Jukka, Raivio, Minna, Tienari, Pentti, Rinne, Juha, Kallionpää, Roosa, Partanen, Juulia, Ziemann, Adam, Smaoui, Nizar, Lehtonen, Anne, Eaton, Susan, Runz, Heiko, Lahdenperä, Sanni, Bowers, Natalie, Teng, Edmond, Xu, Fanli, Addis, Laura, Eicher, John, Li, Qingqin S., He, Karen, Khramtsova, Ekaterina, Färkkilä, Martti, Koskela, Jukka, Pikkarainen, Sampsa, Jussila, Airi, Kaukinen, Katri, Blomster, Timo, Kiviniemi, Mikko, Voutilainen, Markku, Lu, Tim, McCarthy, Linda, Hart, Amy, Guan, Meijian, Miller, Jason, Kalpala, Kirsi, Miller, Melissa, Eklund, Kari, Palomäki, Antti, Isomäki, Pia, Pirilä, Laura, Kaipiainen-Seppänen, Oili, Huhtakangas, Johanna, Mars, Nina, Lertratanakul, Apinya, Hochfeld, Marla, Gordillo, Jorge Esparza, Farias, Fabiana, Bing, Nan, Laitinen, Tarja, Pelkonen, Margit, Kauppi, Paula, Kankaanranta, Hannu, Harju, Terttu, Lahesmaa, Riitta, Chen, Hubert, Betts, Joanna, Mishra, Rajashree, Mouded, Majd, Ngo, Debby, Niiranen, Teemu, Vaura, Felix, Salomaa, Veikko, Metsärinne, Kaj, Aittokallio, Jenni, Hernesniemi, Jussi, Gordin, Daniel, Sinisalo, Juha, Taskinen, Marja-Riitta, Tuomi, Tiinamaija, Hiltunen, Timo, Elliott, Amanda, Reeve, Mary Pat, Ruotsalainen, Sanni, Paul, Dirk, Chu, Audrey, Reilly, Dermot, Mendelson, Mike, Parkkinen, Jaakko, Meretoja, Tuomo, Joensuu, Heikki, Mattson, Johanna, Salminen, Eveliina, Auranen, Annika, Karihtala, Peeter, Auvinen, Päivi, Elenius, Klaus, Pitkänen, Esa, Popovic, Relja, Fabre, Margarete, Schutzman, Jennifer, Kulkarni, Diptee, Porello, Alessandro, Loboda, Andrey, Lehtonen, Heli, McDonough, Stefan, Vuoti, Sauli, Kaarniranta, Kai, Turunen, Joni A., Ollila, Terhi, Uusitalo, Hannu, Karjalainen, Juha, Liu, Mengzhen, Loomis, Stephanie, Strauss, Erich, Chen, Hao, Tasanen, Kaisa, Huilaja, Laura, Hannula-Jouppi, Katariina, Salmi, Teea, Peltonen, Sirkku, Koulu, Leena, Choy, David, Wu, Ying, Pussinen, Pirkko, Salminen, Aino, Salo, Tuula, Rice, David, Nieminen, Pekka, Palotie, Ulla, Siponen, Maria, Suominen, Liisa, Mäntylä, Päivi, Gursoy, Ulvi, Anttonen, Vuokko, Sipilä, Kirsi, Laivuori, Hannele, Kurra, Venla, Kotaniemi-Talonen, Laura, Heikinheimo, Oskari, Kalliala, Ilkka, Aaltonen, Lauri, Jokimaa, Varpu, Vääräsmäki, Marja, Uimari, Outi, Morin-Papunen, Laure, Niinimäki, Maarit, Piltonen, Terhi, Kivinen, Katja, Widen, Elisabeth, Tukiainen, Taru, Välimäki, Niko, Laakkonen, Eija, Tyrmi, Jaakko, Silven, Heidi, Sliz, Eeva, Arffman, Riikka, Savukoski, Susanna, Laisk, Triin, Pujol, Natalia, Kumar, Janet, Hovatta, Iiris, Isometsä, Erkki, Ollila, Hanna, Suvisaari, Jaana, Mäkitie, Antti, Bizaki-Vallaskangas, Argyro, Toppila-Salmi, Sanna, Willberg, Tytti, Saarentaus, Elmo, Aarnisalo, Antti, Rahikkala, Elisa, Aittomäki, Kristiina, Åberg, Fredrik, Kurki, Mitja, Havulinna, Aki, Mehtonen, Juha, Palta, Priit, Hassan, Shabbeer, Della Briotta Parolo, Pietro, Zhou, Wei, Maasha, Mutaamba, Lemmelä, Susanna, Rivas, Manuel, Liu, Aoxing, Lehisto, Arto, Ganna, Andrea, Llorens, Vincent, Heyne, Henrike, Rämö, Joel, Rodosthenous, Rodos, Strausz, Satu, Palotie, Tuula, Palin, Kimmo, Garcia-Tabuenca, Javier, Siirtola, Harri, Kiiskinen, Tuomo, Lee, Jiwoo, Tsuo, Kristin, Hyvärinen, Kati, Ritari, Jarmo, Pylkäs, Katri, Karjalainen, Minna, Mantere, Tuomo, Kangasniemi, Eeva, Heikkinen, Sami, Pitkänen, Nina, Lessard, Samuel, Chatelain, Clément, Kallio, Lila, Wahlfors, Tiina, Punkka, Eero, Siltanen, Sanna, Kuopio, Teijo, Jalanko, Anu, Shen, Huei-Yi, Kajanne, Risto, Aavikko, Mervi, Cooper, Helen, Öller, Denise, Leinonen, Rasko, Palin, Henna, Linna, Malla-Maria, Kanai, Masahiro, Zheng, Zhili, Lahtela, L. Elisa, Kaunisto, Mari, Kilpeläinen, Elina, Sipilä, Timo P., Dada, Oluwaseun Alexander, Ghazal, Awaisa, Kytölä, Anastasia, Weldatsadik, Rigbe, Donner, Kati, Loukola, Anu, Laiho, Päivi, Sistonen, Tuuli, Kaiharju, Essi, Laukkanen, Markku, Järvensivu, Elina, Lähteenmäki, Sini, Männikkö, Lotta, Wong, Regis, Toivola, Auli, Brunfeldt, Minna, Mattsson, Hannele, Koskelainen, Sami, Hiekkalinna, Tero, Paajanen, Teemu, Luo, Shuang, Padmanabhuni, Shanmukha Sampath, Niemi, Marianna, Gracia-Tabuenca, Javier, Helminen, Mika, Luukkaala, Tiina, Vähätalo, Iida, Tammerluoto, Jyrki, Smith, Sarah, Southerington, Tom, Lehto, Petri, Ryu, Justine, Rämö, Joel T., Jurgens, Sean J., Sanna-Cherchi, Simone, Bauer, Kenneth A., Haj, Amelia, Choi, Seung Hoan, Ellinor, Patrick T., and Bendapudi, Pavan K.

Published
2024
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2. Low-frequency inherited complement receptor variants are associated with purpura fulminans

Author

Bendapudi, Pavan K., Nazeen, Sumaiya, Ryu, Justine, Söylemez, Onuralp, Robbins, Alissa, Rouaisnel, Betty, O’Neil, Jillian K., Pokhriyal, Ruchika, Yang, Moua, Colling, Meaghan, Pasko, Bryce, Bouzinier, Michael, Tomczak, Lindsay, Collier, Lindsay, Barrios, David, Ram, Sanjay, Toth-Petroczy, Agnes, Krier, Joel, Fieg, Elizabeth, Dzik, Walter H., Hudspeth, James C., Pozdnyakova, Olga, Nardi, Valentina, Knight, James, Maas, Richard, Sunyaev, Shamil, and Losman, Julie-Aurore

Published
2024
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3. A phase 2 trial of CD24Fc for prevention of graft-versus-host disease

Author

Magenau, John, Jaglowski, Samantha, Uberti, Joseph, Farag, Sherif S., Riwes, Mary Mansour, Pawarode, Attaphol, Anand, Sarah, Ghosh, Monalisa, Maciejewski, John, Braun, Thomas, Devenport, Martin, Lu, Susan, Banerjee, Bhramori, DaSilva, Carolyn, Devine, Steven, Zhang, Mei-Jie, Burns, Linda J., Liu, Yang, Zheng, Pan, and Reddy, Pavan

Published
2024
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5. Mechanisms of response and resistance to combined decitabine and ipilimumab for advanced myeloid disease

Author

Penter, Livius, Liu, Yang, Wolff, Jacquelyn O., Yang, Lin, Taing, Len, Jhaveri, Aashna, Southard, Jackson, Patel, Manishkumar, Cullen, Nicole M., Pfaff, Kathleen L., Cieri, Nicoletta, Oliveira, Giacomo, Kim-Schulze, Seunghee, Ranasinghe, Srinika, Leonard, Rebecca, Robertson, Taylor, Morgan, Elizabeth A., Chen, Helen X., Song, Minkyung H., Thurin, Magdalena, Li, Shuqiang, Rodig, Scott J., Cibulskis, Carrie, Gabriel, Stacey, Bachireddy, Pavan, Ritz, Jerome, Streicher, Howard, Neuberg, Donna S., Hodi, F. Stephen, Davids, Matthew S., Gnjatic, Sacha, Livak, Kenneth J., Altreuter, Jennifer, Michor, Franziska, Soiffer, Robert J., Garcia, Jacqueline S., and Wu, Catherine J.

Published
2023
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7. Effective Gene Therapy for Hemophilia a: Novel Re-Dosable Non-Viral Formulation That Provides Stable, and Durable FVIII Expression with Improved Tolerability

Author

Truong, Brian, primary, Hajj, Khal, additional, Schwerk, Johannes, additional, Zhang, Dongyang, additional, Tamayo, Johnnatan, additional, Guzelsoy, Gizem, additional, Kubicki, Joseph, additional, Davis, Alicia, additional, Huang, Lijun, additional, Vemuri, Gopi, additional, Johnson, Kevin, additional, Smith, Dan, additional, Bendor, Jordan, additional, Li, Mu, additional, Goolyam, Manjunath, additional, Abernathy, Daniel, additional, Nyshadham, Pranav, additional, Espinoza, Fernando, additional, Burrascano, Michelle, additional, Yen, James, additional, Briseno, Kevin, additional, Tong, Min, additional, Beck, Jen, additional, Lucas, Joseph, additional, Battiprolu, Pavan, additional, Bennett, Michael, additional, Madison, Blair, additional, Warner, Brent, additional, Ostertag, Eric, additional, and Rychak, Joshua, additional

Published
2023
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8. Thrombosis risk in single- and double-heterozygous carriers of factor V Leiden and prothrombin G20210A in FinnGen and the UK Biobank

Author

Ryu, Justine, Rämö, Joel T., Jurgens, Sean J., Palotie, Aarno, Daly, Mark, Riley-Gills, Bridget, Jacob, Howard, Viollet, Coralie, Petrovski, Slavé, Chen, Chia-Yen, John, Sally, Okafo, George, Plenge, Robert, Maranville, Joseph, McCarthy, Mark, Pendergrass, Rion, Ehm, Margaret G., Auro, Kirsi, Longerich, Simonne, Mälarstig, Anders, Vlahiotis, Anna, Klinger, Katherine, Chatelain, Clement, Gossel, Matthias, Estrada, Karol, Graham, Robert, Waterworth, Dawn, O´Donnell, Chris, Renaud, Nicole, Mäkelä, Tomi P., Kaprio, Jaakko, Ruddock, Minna, Virolainen, Petri, Hakanen, Antti, Kilpi, Terhi, Perola, Markus, Partanen, Jukka, Raivio, Taneli, Tikkanen, Jani, Serpi, Raisa, Kristiansson, Kati, Kosma, Veli-Matti, Laukkanen, Jari, Hautalahti, Marco, Tuovila, Outi, Waring, Jeffrey, Riley-Gillis, Bridget, Rahimov, Fedik, Tachmazidou, Ioanna, Chen, Chia-Yen, Ding, Zhihao, Jung, Marc, Tuoken, Hanati, Biswas, Shameek, Pendergrass, Rion, Ehm, Margaret G., Pulford, David, Raghavan, Neha, Huertas-Vazquez, Adriana, Sul, Jae-Hoon, Mälarstig, Anders, Hu, Xinli, Hedman, Åsa, Klinger, Katherine, Graham, Robert, Waterworth, Dawn, Renaud, Nicole, Obeidat, Ma´en, Chung, Jonathan, Zierer, Jonas, Niemi, Mari, Ripatti, Samuli, Schleutker, Johanna, Perola, Markus, Arvas, Mikko, Carpén, Olli, Hinttala, Reetta, Kettunen, Johannes, Mannermaa, Arto, Aalto-Setälä, Katriina, Kähönen, Mika, Laukkanen, Jari, Mäkelä, Johanna, Kälviäinen, Reetta, Julkunen, Valtteri, Soininen, Hilkka, Remes, Anne, Hiltunen, Mikko, Peltola, Jukka, Raivio, Minna, Tienari, Pentti, Rinne, Juha, Kallionpää, Roosa, Partanen, Juulia, Ziemann, Adam, Smaoui, Nizar, Lehtonen, Anne, Eaton, Susan, Runz, Heiko, Lahdenperä, Sanni, Biswas, Shameek, Bowers, Natalie, Teng, Edmond, Pendergrass, Rion, Xu, Fanli, Pulford, David, Auro, Kirsi, Addis, Laura, Eicher, John, Li, Qingqin S., He, Karen, Khramtsova, Ekaterina, Raghavan, Neha, Färkkilä, Martti, Koskela, Jukka, Pikkarainen, Sampsa, Jussila, Airi, Kaukinen, Katri, Blomster, Timo, Kiviniemi, Mikko, Voutilainen, Markku, Daly, Mark, Waring, Jeffrey, Smaoui, Nizar, Rahimov, Fedik, Lehtonen, Anne, Lu, Tim, Bowers, Natalie, Pendergrass, Rion, McCarthy, Linda, Hart, Amy, Guan, Meijian, Miller, Jason, Kalpala, Kirsi, Miller, Melissa, Hu, Xinli, Eklund, Kari, Palomäki, Antti, Isomäki, Pia, Pirilä, Laura, Kaipiainen-Seppänen, Oili, Huhtakangas, Johanna, Mars, Nina, Waring, Jeffrey, Rahimov, Fedik, Lertratanakul, Apinya, Smaoui, Nizar, Lehtonen, Anne, Viollet, Coralie, Hochfeld, Marla, Bowers, Natalie, Pendergrass, Rion, Gordillo, Jorge Esparza, Auro, Kirsi, Waterworth, Dawn, Farias, Fabiana, Kalpala, Kirsi, Bing, Nan, Hu, Xinli, Laitinen, Tarja, Pelkonen, Margit, Kauppi, Paula, Kankaanranta, Hannu, Harju, Terttu, Lahesmaa, Riitta, Smaoui, Nizar, Viollet, Coralie, Eaton, Susan, Chen, Hubert, Pendergrass, Rion, Bowers, Natalie, Betts, Joanna, Auro, Kirsi, Mishra, Rajashree, Mouded, Majd, Ngo, Debby, Niiranen, Teemu, Vaura, Felix, Salomaa, Veikko, Metsärinne, Kaj, Aittokallio, Jenni, Kähönen, Mika, Hernesniemi, Jussi, Gordin, Daniel, Sinisalo, Juha, Taskinen, Marja-Riitta, Tuomi, Tiinamaija, Hiltunen, Timo, Laukkanen, Jari, Elliott, Amanda, Reeve, Mary Pat, Ruotsalainen, Sanni, Paul, Dirk, Bowers, Natalie, Pendergrass, Rion, Chu, Audrey, Auro, Kirsi, Reilly, Dermot, Mendelson, Mike, Parkkinen, Jaakko, Miller, Melissa, Meretoja, Tuomo, Joensuu, Heikki, Carpén, Olli, Mattson, Johanna, Salminen, Eveliina, Auranen, Annika, Karihtala, Peeter, Auvinen, Päivi, Elenius, Klaus, Schleutker, Johanna, Pitkänen, Esa, Mars, Nina, Daly, Mark, Popovic, Relja, Waring, Jeffrey, Riley-Gillis, Bridget, Lehtonen, Anne, Fabre, Margarete, Schutzman, Jennifer, Bowers, Natalie, Pendergrass, Rion, Kulkarni, Diptee, Auro, Kirsi, Porello, Alessandro, Loboda, Andrey, Lehtonen, Heli, McDonough, Stefan, Vuoti, Sauli, Kaarniranta, Kai, Turunen, Joni A., Ollila, Terhi, Uusitalo, Hannu, Karjalainen, Juha, Pitkänen, Esa, Liu, Mengzhen, Runz, Heiko, Loomis, Stephanie, Strauss, Erich, Bowers, Natalie, Chen, Hao, Pendergrass, Rion, Tasanen, Kaisa, Huilaja, Laura, Hannula-Jouppi, Katariina, Salmi, Teea, Peltonen, Sirkku, Koulu, Leena, Smaoui, Nizar, Rahimov, Fedik, Lehtonen, Anne, Choy, David, Pendergrass, Rion, Waterworth, Dawn, Kalpala, Kirsi, Wu, Ying, Pussinen, Pirkko, Salminen, Aino, Salo, Tuula, Rice, David, Nieminen, Pekka, Palotie, Ulla, Siponen, Maria, Suominen, Liisa, Mäntylä, Päivi, Gursoy, Ulvi, Anttonen, Vuokko, Sipilä, Kirsi, Pendergrass, Rion, Laivuori, Hannele, Kurra, Venla, Kotaniemi-Talonen, Laura, Heikinheimo, Oskari, Kalliala, Ilkka, Aaltonen, Lauri, Jokimaa, Varpu, Kettunen, Johannes, Vääräsmäki, Marja, Uimari, Outi, Morin-Papunen, Laure, Niinimäki, Maarit, Piltonen, Terhi, Kivinen, Katja, Widen, Elisabeth, Tukiainen, Taru, Reeve, Mary Pat, Daly, Mark, Välimäki, Niko, Laakkonen, Eija, Tyrmi, Jaakko, Silven, Heidi, Sliz, Eeva, Arffman, Riikka, Savukoski, Susanna, Laisk, Triin, Pujol, Natalia, Liu, Mengzhen, Riley-Gillis, Bridget, Pendergrass, Rion, Kumar, Janet, Auro, Kirsi, Hovatta, Iiris, Chen, Chia-Yen, Isometsä, Erkki, Ollila, Hanna, Suvisaari, Jaana, Mäkitie, Antti, Bizaki-Vallaskangas, Argyro, Toppila-Salmi, Sanna, Willberg, Tytti, Saarentaus, Elmo, Aarnisalo, Antti, Salminen, Eveliina, Rahikkala, Elisa, Kettunen, Johannes, Aittomäki, Kristiina, Åberg, Fredrik, Kurki, Mitja, Ripatti, Samuli, Daly, Mark, Karjalainen, Juha, Havulinna, Aki, Mehtonen, Juha, Palta, Priit, Hassan, Shabbeer, Della Briotta Parolo, Pietro, Zhou, Wei, Maasha, Mutaamba, Hassan, Shabbeer, Lemmelä, Susanna, Rivas, Manuel, Palotie, Aarno, Liu, Aoxing, Lehisto, Arto, Ganna, Andrea, Llorens, Vincent, Laivuori, Hannele, Tukiainen, Taru, Reeve, Mary Pat, Heyne, Henrike, Mars, Nina, Rämö, Joel, Saarentaus, Elmo, Ollila, Hanna, Rodosthenous, Rodos, Strausz, Satu, Palotie, Tuula, Palin, Kimmo, Garcia-Tabuenca, Javier, Siirtola, Harri, Kiiskinen, Tuomo, Lee, Jiwoo, Tsuo, Kristin, Elliott, Amanda, Kristiansson, Kati, Arvas, Mikko, Hyvärinen, Kati, Ritari, Jarmo, Carpén, Olli, Kettunen, Johannes, Pylkäs, Katri, Sliz, Eeva, Karjalainen, Minna, Mantere, Tuomo, Kangasniemi, Eeva, Heikkinen, Sami, Mannermaa, Arto, Laakkonen, Eija, Pitkänen, Nina, Lessard, Samuel, Chatelain, Clément, Kallio, Lila, Wahlfors, Tiina, Partanen, Jukka, Punkka, Eero, Serpi, Raisa, Siltanen, Sanna, Kosma, Veli-Matti, Kuopio, Teijo, Jalanko, Anu, Shen, Huei-Yi, Kajanne, Risto, Aavikko, Mervi, Cooper, Helen, Öller, Denise, Leinonen, Rasko, Palin, Henna, Linna, Malla-Maria, Kurki, Mitja, Karjalainen, Juha, Della Briotta Parolo, Pietro, Lehisto, Arto, Mehtonen, Juha, Zhou, Wei, Kanai, Masahiro, Maasha, Mutaamba, Zheng, Zhili, Laivuori, Hannele, Havulinna, Aki, Lemmelä, Susanna, Kiiskinen, Tuomo, Lahtela, L. Elisa, Kaunisto, Mari, Kilpeläinen, Elina, Sipilä, Timo P., Dada, Oluwaseun Alexander, Ghazal, Awaisa, Kytölä, Anastasia, Weldatsadik, Rigbe, Ruotsalainen, Sanni, Donner, Kati, Sipilä, Timo P., Loukola, Anu, Laiho, Päivi, Sistonen, Tuuli, Kaiharju, Essi, Laukkanen, Markku, Järvensivu, Elina, Lähteenmäki, Sini, Männikkö, Lotta, Wong, Regis, Toivola, Auli, Brunfeldt, Minna, Mattsson, Hannele, Kristiansson, Kati, Lemmelä, Susanna, Koskelainen, Sami, Hiekkalinna, Tero, Paajanen, Teemu, Palta, Priit, Luo, Shuang, Laitinen, Tarja, Reeve, Mary Pat, Padmanabhuni, Shanmukha Sampath, Niemi, Marianna, Siirtola, Harri, Gracia-Tabuenca, Javier, Helminen, Mika, Luukkaala, Tiina, Vähätalo, Iida, Tammerluoto, Jyrki, Hautalahti, Marco, Mäkelä, Johanna, Smith, Sarah, Southerington, Tom, Lehto, Petri, Niiranen, Teemu, Sanna-Cherchi, Simone, Bauer, Kenneth A., Haj, Amelia, Choi, Seung Hoan, Palotie, Aarno, Daly, Mark, Ellinor, Patrick T., and Bendapudi, Pavan K.

Abstract

•Population-scale genomics (N = 937 939) allowed assembly of a large FVL/PTGM double-heterozygous cohort while mitigating ascertainment bias.•FVL/PTGM DH appeared to be more common than FVL homozygosity and conferred a similar risk of venous thrombosis.

Published
2024
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9. Mechanisms of response and resistance to combined decitabine and ipilimumab for advanced myeloid disease

Author

Livius Penter, Yang Liu, Jacquelyn O. Wolff, Lin Yang, Len Taing, Aashna Jhaveri, Jackson Southard, Manishkumar Patel, Nicole M. Cullen, Kathleen L. Pfaff, Nicoletta Cieri, Giacomo Oliveira, Seunghee Kim-Schulze, Srinika Ranasinghe, Rebecca Leonard, Taylor Robertson, Elizabeth A. Morgan, Helen X. Chen, Minkyung H. Song, Magdalena Thurin, Shuqiang Li, Scott J. Rodig, Carrie Cibulskis, Stacey Gabriel, Pavan Bachireddy, Jerome Ritz, Howard Streicher, Donna S. Neuberg, F. Stephen Hodi, Matthew S. Davids, Sacha Gnjatic, Kenneth J. Livak, Jennifer Altreuter, Franziska Michor, Robert J. Soiffer, Jacqueline S. Garcia, and Catherine J. Wu

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Abstract

The challenge of eradicating leukemia in patients with acute myelogenous leukemia (AML) after initial cytoreduction has motivated modern efforts to combine synergistic active modalities including immunotherapy. Recently, the ETCTN/CTEP 10026 study tested the combination of the DNA methyltransferase inhibitor decitabine together with the immune checkpoint inhibitor ipilimumab for AML/myelodysplastic syndrome (MDS) either after allogeneic hematopoietic stem cell transplantation (HSCT) or in the HSCT-naïve setting. Integrative transcriptome-based analysis of 304 961 individual marrow-infiltrating cells for 18 of 48 subjects treated on study revealed the strong association of response with a high baseline ratio of T to AML cells. Clinical responses were predominantly driven by decitabine-induced cytoreduction. Evidence of immune activation was only apparent after ipilimumab exposure, which altered CD4+ T-cell gene expression, in line with ongoing T-cell differentiation and increased frequency of marrow-infiltrating regulatory T cells. For post-HSCT samples, relapse could be attributed to insufficient clearing of malignant clones in progenitor cell populations. In contrast to AML/MDS bone marrow, the transcriptomes of leukemia cutis samples from patients with durable remission after ipilimumab monotherapy showed evidence of increased infiltration with antigen-experienced resident memory T cells and higher expression of CTLA-4 and FOXP3. Altogether, activity of combined decitabine and ipilimumab is impacted by cellular expression states within the microenvironmental niche of leukemic cells. The inadequate elimination of leukemic progenitors mandates urgent development of novel approaches for targeting these cell populations to generate long-lasting responses. This trial was registered at www.clinicaltrials.gov as #NCT02890329.

Published
2023

10. MAGIC biomarkers predict long-term outcomes for steroid-resistant acute GVHD

Author

Major-Monfried, Hannah, Renteria, Anne S., Pawarode, Attaphol, Reddy, Pavan, Ayuk, Francis, Holler, Ernst, Efebera, Yvonne A., Hogan, William J., Wölfl, Matthias, Qayed, Muna, Hexner, Elizabeth O., Wudhikarn, Kitsada, Ordemann, Rainer, Young, Rachel, Shah, Jay, Hartwell, Matthew J., Chaudhry, Mohammed S., Aziz, Mina, Etra, Aaron, Yanik, Gregory A., Kröger, Nicolaus, Weber, Daniela, Chen, Yi-Bin, Nakamura, Ryotaro, Rösler, Wolf, Kitko, Carrie L., Harris, Andrew C., Pulsipher, Michael, Reshef, Ran, Kowalyk, Steven, Morales, George, Torres, Ivan, Özbek, Umut, Ferrara, James L.M., and Levine, John E.

Published
2018
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14. Impact of CTLA4 genotype and other immune response gene polymorphisms on outcomes after single umbilical cord blood transplantation

Author

Cunha, Renato, Zago, Marco A., Querol, Sergio, Volt, Fernanda, Ruggeri, Annalisa, Sanz, Guillermo, Pouthier, Fabienne, Kogler, Gesine, Vicario, José L., Bergamaschi, Paola, Saccardi, Riccardo, Lamas, Carmen H., Díaz-de-Heredia, Cristina, Michel, Gerard, Bittencourt, Henrique, Tavella, Marli, Panepucci, Rodrigo A., Fernandes, Francisco, Pavan, Julia, Gluckman, Eliane, and Rocha, Vanderson

Published
2017
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15. Lung parenchyma-derived IL-6 promotes IL-17A–dependent acute lung injury after allogeneic stem cell transplantation

Author

Varelias, Antiopi, Gartlan, Kate H., Kreijveld, Ellen, Olver, Stuart D., Lor, Mary, Kuns, Rachel D., Lineburg, Katie E., Teal, Bianca E., Raffelt, Neil C., Cheong, Melody, Alexander, Kylie A., Koyama, Motoko, Markey, Kate A., Sturgeon, Elise, Leach, Justine, Reddy, Pavan, Kennedy, Glen A., Yanik, Gregory A., Blazar, Bruce R., Tey, Siok-Keen, Clouston, Andrew D., MacDonald, Kelli P.A., Cooke, Kenneth R., and Hill, Geoffrey R.

Published
2015
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17. Coagulation Factor XII Is Activated Via Noncanonical Binding to Platelet Integrin αIIbβ3

Author

Chaudhry, Sharjeel, primary, Burton, Randall, additional, Serrata, Matthew, additional, Feingold, Louis, additional, Tomczak, Lindsay, additional, Collier, Lindsay, additional, Laprise, Dylan, additional, Enjyoji, Keiichi, additional, Kaushik, Virendar, additional, Bertovich, Dylan, additional, Burgin, Alex, additional, and Bendapudi, Pavan K., additional

Published
2022
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18. Development of a Standardized, DNA-Based Next Generation Sequencing Assay for Assessment of Measurable Residual Disease (MRD) in Acute Myeloid Leukemia (AML) As the Primary Endpoint in the Agility Study

Author

Carvajal, Luis A., primary, Hood, Tressa, additional, Bevan, Yana, additional, Dillon, Richard, additional, Potter, Nicola, additional, Thomas, Ian, additional, Johnson, Sean, additional, Othman, Jad, additional, Gilkes, Amanda, additional, Russell, Nigel H., additional, Sikorski, Adam, additional, Ellis, Pete, additional, Marsico, Giovanni, additional, Jones, Greg, additional, MacKenzie, Crystal, additional, To, Zung, additional, DiMartino, Jorge, additional, and Kumar, Pavan, additional

Published
2022
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19. Five-Year Follow-up of the Phase I/II Discontinuation Trial of Imatinib after Pioglitazone (EDI-PIO) in Chronic Myeloid Leukemia Patients in Deep Molecular Response

Author

Pagnano, Katia B, primary, Lopes, Ana Beatriz Pascoal, additional, Miranda, Eliana C M Cristina Martins, additional, Delamain, Marcia, additional, Duarte, Gislaine B O, additional, Medina, Samuel de Souza, additional, Pericole, Fernando Vieira, additional, Amarante, Guilherme Brasil Duffles, additional, Duarte, Bruno K, additional, Pavan, Graziele, additional, Toni, Isabella Macedo, additional, De Paula, Erich V, additional, and Souza, Carmino Antonio, additional

Published
2022
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21. Expansion of a CD8+ Temra Population and Activating T-Cell Interactions Characterize the Graft Versus Leukemia Response in Relapsed AML

Author

Maurer, Katie, primary, Park, Cameron Y., additional, Borji, Mehdi, additional, Mani, Shouvik, additional, Southard, Jackson, additional, Farhi, Samouil L., additional, Abbondanza, Domenic, additional, Li, Shuqiang, additional, Livak, Kenneth J., additional, Ritz, Jerome, additional, Soiffer, Robert J., additional, Bachireddy, Pavan, additional, Wu, Catherine J., additional, and Azizi, Elham, additional

Published
2022
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22. Use of Plasmic Scores to Aid Diagnosis of aHUS: A Real-World Analysis of Hospitalized Patients from the Premier Healthcare Database

Author

Gasteyger, Christoph, primary, Uriol-Rivera, Miguel G, additional, Ávila, Ana I, additional, Makar, Robert S, additional, Ernst, Frank R, additional, Booth III, John N, additional, Comas, Angels, additional, Lum, Ching, additional, Tomazos, Ioannis, additional, Wang, Yan, additional, and Bendapudi, Pavan K., additional

Published
2022
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23. A Machine-Learning Derived Red Blood Cell Morphology Tool Enables Differential Diagnosis and Novel Single-Cell Analyses

Author

Foy, Brody, primary, Stefely, Jonathan, additional, Bendapudi, Pavan K., additional, Hasserjian, Robert P., additional, Al-Samkari, Hanny, additional, Louissaint, Abner, additional, Fitzpatrick, Megan J, additional, Hutchison, Bailey, additional, Mow, Christopher, additional, Collins, Julia, additional, Patel, Hasmukh P., additional, Patel, Chhaya, additional, Patel, Nikita, additional, Ho, Samantha, additional, Kaufman, Richard M, additional, Dzik, Walter, additional, Higgins, John M., additional, and Makar, Robert S, additional

Published
2022
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28. Five-Year Follow-up of the Phase I/II Discontinuation Trial of Imatinib after Pioglitazone (EDI-PIO) in Chronic Myeloid Leukemia Patients in Deep Molecular Response

Author

Katia B Pagnano, Ana Beatriz Pascoal Lopes, Eliana C M Cristina Martins Miranda, Marcia Delamain, Gislaine B O Duarte, Samuel de Souza Medina, Fernando Vieira Pericole, Guilherme Brasil Duffles Amarante, Bruno K Duarte, Graziele Pavan, Isabella Macedo Toni, Erich V De Paula, and Carmino Antonio Souza

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Published
2022

31. A Machine-Learning Derived Red Blood Cell Morphology Tool Enables Differential Diagnosis and Novel Single-Cell Analyses

Author

Brody Foy, Jonathan Stefely, Pavan K. Bendapudi, Robert P. Hasserjian, Hanny Al-Samkari, Abner Louissaint, Megan J Fitzpatrick, Bailey Hutchison, Christopher Mow, Julia Collins, Hasmukh P. Patel, Chhaya Patel, Nikita Patel, Samantha Ho, Richard M Kaufman, Walter Dzik, John M. Higgins, and Robert S Makar

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Published
2022

32. Development of a Standardized, DNA-Based Next Generation Sequencing Assay for Assessment of Measurable Residual Disease (MRD) in Acute Myeloid Leukemia (AML) As the Primary Endpoint in the Agility Study

Author

Luis A. Carvajal, Tressa Hood, Yana Bevan, Richard Dillon, Nicola Potter, Ian Thomas, Sean Johnson, Jad Othman, Amanda Gilkes, Nigel H. Russell, Adam Sikorski, Pete Ellis, Giovanni Marsico, Greg Jones, Crystal MacKenzie, Zung To, Jorge DiMartino, and Pavan Kumar

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Published
2022

34. Rare Variant Genetic Association Study for Transplant-Associated Thrombotic Microangiopathy (TA-TMA) Via Whole Exome Sequencing

Author

Zhang, Zhihui, primary, Wu, Qian Vicky, additional, Amos, Christopher I, additional, Liu, Yanhong, additional, Wei, Hong, additional, Cheng, Chao, additional, Tsavachidis, Spiridon, additional, Bryce, Angela, additional, Sartain, Sarah E, additional, Martinez, Caridad A., additional, Afshar-Kharghan, Vahid, additional, Dong, Jing-fei, additional, Bhatraju, Pavan, additional, Martin, Paul J, additional, Lee, Stephanie J., additional, Makar, Robert S., additional, Bendapudi, Pavan K., additional, and Li, Ang, additional

Published
2021
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35. Molecular and cellular features of CTLA-4 blockade for relapsed myeloid malignancies after transplantation

Author

Matthew S. Davids, Robert J. Soiffer, Emma S. Hathaway, F. Stephen Hodi, Pavan Bachireddy, Magdalena Thurin, Vincent T. Ho, Wandi Zhang, Sarah Nikiforow, Nicoletta Cieri, Jerome Ritz, Stacey Gabriel, Mariano Severgnini, Aashna Jhaveri, X. Shirley Liu, Haesook T. Kim, Jingxin Fu, Kenneth J. Livak, Sacha Gnjatic, Scott J. Rodig, Alexandra Savell, Philippe Armand, Catherine J. Wu, Teddy Huang, Joseph H. Antin, Corey Cutler, Carrie Cibulskis, Livius Penter, Shuqiang Li, Howard Streicher, Donna Neuberg, Srinika Ranasinghe, Matthew Nazzaro, Yi Zhang, Emily M. Thrash, Helen X. Chen, John Koreth, and Seunghee Kim-Schulze

Subjects
Male, Myeloid, BLOOD COMMENTARY, medicine.medical_treatment, Immunology, Ipilimumab, Hematopoietic stem cell transplantation, CD8-Positive T-Lymphocytes, Biochemistry, medicine, Humans, CTLA-4 Antigen, Gene Expression Regulation, Leukemic, business.industry, Allogeneic Cells, Hematopoietic Stem Cell Transplantation, Cell Biology, Hematology, Immune checkpoint, Neoplasm Proteins, Blockade, Transplantation, medicine.anatomical_structure, Leukemia, Myeloid, CTLA-4, Cancer research, Female, Nivolumab, business, medicine.drug
Abstract

Relapsed myeloid disease after allogeneic stem cell transplantation (HSCT) remains largely incurable. We previously demonstrated the potent activity of immune checkpoint blockade in this clinical setting with ipilimumab or nivolumab. To define the molecular and cellular pathways by which CTLA-4 blockade with ipilimumab can reinvigorate an effective graft-versus-leukemia (GVL) response, we integrated transcriptomic analysis of leukemic biopsies with immunophenotypic profiling of matched peripheral blood samples collected from patients treated with ipilimumab following HSCT on the Experimental Therapeutics Clinical Trials Network 9204 trial. Response to ipilimumab was associated with transcriptomic evidence of increased local CD8+ T-cell infiltration and activation. Systemically, ipilimumab decreased naïve and increased memory T-cell populations and increased expression of markers of T-cell activation and costimulation such as PD-1, HLA-DR, and ICOS, irrespective of response. However, responding patients were characterized by higher turnover of T-cell receptor sequences in peripheral blood and showed increased expression of proinflammatory chemokines in plasma that was further amplified by ipilimumab. Altogether, these data highlight the compositional T-cell shifts and inflammatory pathways induced by ipilimumab both locally and systemically that associate with successful GVL outcomes. This trial was registered at www.clinicaltrials.gov as #NCT01822509.

Published
2021

40. IKAROS and CK2 regulate expression of BCL-XL and chemosensitivity in high-risk B-cell acute lymphoblastic leukemia

Author

Kimberly J. Payne, Yuka Imamura Kawasawa, Nathalia Moreno Cury, Zafer Gurel, Gavin P. Robertson, Feng Yue, Raghavendra Gowda, Dhimant Desai, José Andrés Yunes, Jonathon L. Payne, Chunhua Song, Yali Ding, Joseph Schramm, Bi-Hua Tan, Chandrika Gowda, Krishne Gowda, Zhijun Zhao, Vladimir S. Spiegelman, Xiaoguang Lyu, Meixian Xiang, Markus Müschen, Zheng Ge, Ruijun Jeanna Su, Soumya Iyer, Mary H. McGrath, Pavan Kumar Dhanyamraju, Yiping Yang, Sinisa Dovat, Shantu Amin, Mark E. Reeves, and Suming Huang

Subjects
Immunology, bcl-X Protein, Bcl-xL, Biochemistry, Chromatin remodeling, Ikaros Transcription Factor, Mice, Cell Line, Tumor, medicine, Animals, Humans, Doxorubicin, Casein Kinase II, Regulation of gene expression, Antibiotics, Antineoplastic, Lymphoid Neoplasia, biology, Gene Expression Regulation, Leukemic, Cell Biology, Hematology, Precursor Cell Lymphoblastic Leukemia-Lymphoma, medicine.disease, HDAC1, Leukemia, Drug Resistance, Neoplasm, Cancer research, biology.protein, Histone deacetylase, Casein kinase 2, medicine.drug
Abstract

High-risk B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive disease, often characterized by resistance to chemotherapy. A frequent feature of high-risk B-ALL is loss of function of the IKAROS (encoded by the IKZF1 gene) tumor suppressor. Here, we report that IKAROS regulates expression of the BCL2L1 gene (encodes the BCL-XL protein) in human B-ALL. Gain-of-function and loss-of-function experiments demonstrate that IKAROS binds to the BCL2L1 promoter, recruits histone deacetylase HDAC1, and represses BCL2L1 expression via chromatin remodeling. In leukemia, IKAROS’ function is impaired by oncogenic casein kinase II (CK2), which is overexpressed in B-ALL. Phosphorylation by CK2 reduces IKAROS binding and recruitment of HDAC1 to the BCL2L1 promoter. This results in a loss of IKAROS-mediated repression of BCL2L1 and increased expression of BCL-XL. Increased expression of BCL-XL and/or CK2, as well as reduced IKAROS expression, are associated with resistance to doxorubicin treatment. Molecular and pharmacological inhibition of CK2 with a specific inhibitor CX-4945, increases binding of IKAROS to the BCL2L1 promoter and enhances IKAROS-mediated repression of BCL2L1 in B-ALL. Treatment with CX-4945 increases sensitivity to doxorubicin in B-ALL, and reverses resistance to doxorubicin in multidrug-resistant B-ALL. Combination treatment with CX-4945 and doxorubicin show synergistic therapeutic effects in vitro and in preclinical models of high-risk B-ALL. Results reveal a novel signaling network that regulates chemoresistance in leukemia. These data lay the groundwork for clinical testing of a rationally designed, targeted therapy that combines the CK2 inhibitor, CX-4945, with doxorubicin for the treatment of hematopoietic malignancies.

Published
2020

41. A multicenter phase 1 study of nivolumab for relapsed hematologic malignancies after allogeneic transplantation

Author

Yi Bin Chen, Edward D. Ball, Robert J. Soiffer, Vincent T. Ho, Pavan Bachireddy, Corey Cutler, David Avigan, Asad Bashey, Catherine J. Wu, Howard Streicher, Michael Mazzeo, Jerome Ritz, Alexandra Savell, Edwin P. Alyea, Frederick L. Locke, Haesook T. Kim, Philippe Armand, Caitlin Costello, Adrienne Anderson, Alex F. Herrera, Sarah Nikiforow, Rodrigo O. Maegawa, Alexander P. Boardman, Augustine Weber, and Matthew S. Davids

Subjects
Adult, Male, Oncology, medicine.medical_specialty, Programmed Cell Death 1 Receptor, Immunology, Graft vs Host Disease, Kaplan-Meier Estimate, Biochemistry, Antineoplastic Agents, Immunological, Recurrence, Internal medicine, medicine, Humans, Prospective Studies, Treatment Failure, Adverse effect, Prospective cohort study, Aged, Transplantation, business.industry, Hematopoietic Stem Cell Transplantation, Retrospective cohort study, Cell Biology, Hematology, Middle Aged, Allografts, medicine.disease, Clinical trial, Nivolumab, Graft-versus-host disease, Hematologic Neoplasms, Toxicity, Female, business
Abstract

Programmed cell death-1 (PD-1)/programmed death ligand-1 blockade may potentially augment graft-vs-tumor effects following allogeneic hematopoietic cell transplantation (alloHCT), but retrospective studies of anti–PD-1 therapy reported substantial toxicity from graft-versus-host-disease (GVHD). Here, we report the results of a prospective clinical trial of PD-1 blockade for relapsed hematologic malignancies (HMs) after alloHCT (NCT01822509). The primary objective in this phase 1 multicenter, investigator-initiated study was to determine maximum tolerated dose and safety. Secondary objectives were to assess efficacy and immunologic activity. Patients with relapsed HMs following alloHCT were eligible. Nivolumab was administered every 2 weeks until progression or unacceptable toxicity, starting with a 1-mg/kg cohort, with planned deescalation based on toxicity to a 0.5-mg/kg cohort. Twenty-eight patients were treated (n = 19 myeloid, n = 9 lymphoid). Median age was 57 years (range 27-76), and median time from alloHCT to enrollment was 21 months (range 5.6-108.5). Two of 6 patients treated at 1 mg/kg experienced dose-limiting toxicity (DLT) from immune-related adverse events (irAEs). Twenty-two patients were treated at 0.5 mg/kg, and 4 DLTs occurred, including 2 irAEs and 2 with fatal GVHD. The overall response rate in efficacy-evaluable patients was 32% (8/25). With a median follow-up of 11 months, the 1-year progression-free survival and overall survival were 23% and 56%, respectively. In this first prospective clinical trial of an anti–PD-1 antibody for post–alloHCT relapse, GVHD and irAEs occurred, requiring dose deescalation, with only modest antitumor activity. Further studies of anti–PD-1 therapy post–alloHCT may require specific toxicity mitigation strategies. This trial was registered at www.clinicaltrials.gov as #NCT 01822509.

Published
2020

44. The Absence of NLRP6 in Donor T Cells Exacerbates Gvhd

Author

Suto, Masahiro, primary, Matsuki, Eri, additional, Miyata, Masahiro, additional, Sekiguchi, Erika, additional, Tamaki, Hiroya, additional, Tawara, Isao, additional, Peltier, Daniel, additional, Chen, Grace, additional, Ishizawa, Kenichi, additional, Reddy, Pavan, additional, and Toubai, Tomomi, additional

Published
2021
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45. Preclinical Activity of Selective SYK Inhibitors, Entospletinib and Lanraplenib, Alone or Combined with Targeted Agents in Ex Vivo AML Models with Diverse Mutational Backgrounds

Author

Day, Melinda A. L., primary, Sergeev, Philipp, additional, Heckman, Caroline A., additional, Schinzel, Anna, additional, Obholzer, Nikolaus D., additional, Lin, Charles Y., additional, Kumar, Pavan, additional, DiMartino, Jorge, additional, and Saffran, Douglas C., additional

Published
2021
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46. Acute Myeloid Leukemia Patients in Complete Remission with Positive Measurable Residual Disease Prior to Allogeneic Transplant Have Worse Outcomes, Similar to Active Disease Regardless of Conditioning Regimen Intensity and Post-Transplant Cyclophosphamide Administration

Author

Tenneti, Pavan, primary, He, Jiaxian, additional, Ragon, Brittany Knick, additional, Shah, Nilay A., additional, Ai, Jing, additional, Chojecki, Aleksander L., additional, Knight, Thomas G., additional, Avalos, Belinda, additional, Copelan, Edward A., additional, Grunwald, Michael R., additional, and Sanikommu, Srinivasa Reddy R., additional

Published
2021
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48. A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Entospletinib in Combination with Intensive Induction and Consolidation Chemotherapy in Adults with Newly Diagnosed N ucleophosmin 1-mutated Acute Myeloid Leukemia

Author

Byrd, John C., primary, Cortes, Jorge E., additional, Minden, Mark D., additional, Oellerich, Thomas, additional, Stein, Eytan M., additional, Elder, Jenna, additional, Kumar, Pavan, additional, Bray, Gordon, additional, DiMartino, Jorge, additional, and Stock, Wendy, additional

Published
2021
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50. Rare Variant Genetic Association Study for Transplant-Associated Thrombotic Microangiopathy (TA-TMA) Via Whole Exome Sequencing

Author

Vahid Afshar-Kharghan, Angela Bryce, Stephanie J. Lee, Ang Li, Spiridon Tsavachidis, Yanhong Liu, Jing-fei Dong, Pavan K. Bendapudi, Paul J. Martin, Sarah E. Sartain, Robert S. Makar, Hong Wei, Zhihui Zhang, Chao Cheng, Christopher I. Amos, Caridad Martinez, Qian Vicky Wu, and Pavan K. Bhatraju

Subjects
Genetics, Thrombotic microangiopathy, business.industry, Immunology, medicine, Cell Biology, Hematology, medicine.disease, business, Biochemistry, Exome sequencing, Genetic association
Abstract

Introduction: Transplant-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized hematologic complication after allogeneic hematopoietic cell transplantation (HCT). While few studies have reported germline association with rare variants in complement genes using targeted next generation sequencing (NGS) method, they were limited by small sample size (≤40 TMA cases) and lack of analysis of non-complement genes (PMIDs 26603840, 32131130). In the present study, we employed whole exome sequencing (WES) to assess rare variant contribution to the development of TMA in a hypothesis-driven pathway-specific approach. Methods: In the current case-control genetic association study conducted at Fred Hutchinson Cancer Research Center, we selected 100 patients with a diagnosis of TMA and pre-transplant DNA samples (case definition described previously in PMID 30940363, 33836868). We then performed incidence density sampling to randomly select 100 non-TMA controls after allogeneic HCT matching by age, sex, race, and year of HCT. WES (germline variant detection 40x) was conducted using Illumina NovaSeq. Sequence reads were mapped to hg38 reference genome followed by deduplication and base quality score recalibration. Joint-genotyping was performed to call single nucleotide polymorphism (SNPs) and insertion/deletion (indels) using the GATK v3.3 and Atlas2. Variants were filtered during quality control (QC) and variant quality score recalibration (VQSR) and annotated using ANNOVAR and Ensembl VEP. To optimize signal detection by reducing neutral background variation, we defined qualifying variants as those meeting all 3 criteria: 1) novel or rare variants with a minor allele frequency (MAF) We then focused on the exome profiles of 5 a priori selected genetic pathways: complement regulation (17 genes), VWF and coagulation (7 genes), VWF clearance (10 genes), ADAMTS13 mimics or interacting proteins (10 genes), and angiopoietin family and endothelial activation (7 genes). Pathway-based and gene-based collapsing association tests were performed using the Optimized Sequence Kernel Association (SKAT-O) test as an optimal test combining burden test and SKAT. Results: After joint variant calling, 91 TMA cases and 93 non-TMA controls passed all QC filters (Table 1). Among 1,485 variants detected in the 5 pathways after QC, 60 variants (73 total mutations) were considered as qualifying variants with MAF Conclusion: Contrary to the initial hypothesis, we did not observe pathogenic germline rare variants in the complement regulation pathway in patients with TA-TMA. Instead, we found a significant association in the VWF clearance pathway, particularly that of the LRP1 gene. In recent years, researchers have shown that VWF can bind to and activate complement proteins. Impaired VWF clearance could lead to the higher predisposition for complement activation observed in patients with TA-TMA. Future functional studies are needed to determine the impact of VWF clearance on the pathogenesis of the disease. Figure 1 Figure 1. Disclosures Sartain: Alexon Pharamaceuticals: Membership on an entity's Board of Directors or advisory committees. Lee: Incyte: Research Funding; Janssen: Other; Takeda: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Kadmon: Research Funding; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Syndax: Research Funding; AstraZeneca: Research Funding; Amgen: Research Funding.

Published
2021

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