tbuckley/cabot-search huggingface dataset:
Targeting ubiquitin-independent proteasome with small molecule increases susceptibility in pan-KRAS–mutant cancer models
Authors: Shihui Shen, Qiansen Zhang, Yuhan Wang, Hui Chen, Shuangming Gong, Yun Liu, Conghao Gai, Hansen Chen, Enhao Zhu, Bo Yang, Lin Liu, Siyuan Cao, Mengting Zhao, Wenjie Ren, Mengjuan Li, Zhuoya Peng, Lu Zhang, Shaoying Zhang, Juwen Shen, Bianhong Zhang, Patrick K.H. Lee, Kun Li, Lei Li, Huaiyu Yang
Journal: Journal of Clinical Investigation (2025)

Despite advances in the development of direct KRAS inhibitors, KRAS-mutant cancers continue to exhibit resistance to the currently available therapies. Here, we identified REGγ as a mutant KRAS–associated factor that enhanced REGγ transcription through the KRAS intermediate NRF2, suggesting that the REGγ-proteasome is a potential target for pan-KRAS inhibitor development. We elucidated a mechanism involving the KRAS/NRF2/REGγ regulatory axis, which links activated KRAS to the ATP- and ubiquitin-independent proteasome. We subsequently developed RLY01, a REGγ-proteasome inhibitor that effectively suppressed tumor growth in KRAS-mutant cancer models and lung cancer organoids. Notably, the combination of RLY01 and the KRASG12C inhibitor AMG510 exhibited enhanced antitumor efficacy in KRASG12C cancer cells. Collectively, our data support the hypothesis that KRAS mutations enhance the capacity of the REGγ-proteasome by increasing REGγ expression, highlighting the potential of ubiquitin-independent proteasome inhibition as a therapeutic approach for pan-KRAS–mutant cancers.
Post-transfusion activation of coagulation pathways during severe COVID-19 correlates with COVID-19 convalescent plasma antibody profiles
Authors: Svenja Weiss, Hung-Mo Lin, Eric Acosta, Natalia L. Komarova, Ping Chen, Dominik Wodarz, Ian Baine, Ralf Duerr, Ania Wajnberg, Adrian Gervais, Paul Bastard, Jean-Laurent Casanova, Suzanne A. Arinsburg, Talia H. Swartz, Judith A. Aberg, Nicole M. Bouvier, Sean T.H. Liu, Raymond A. Alvarez, Benjamin K. Chen
Journal: Journal of Clinical Investigation (2025)

Early antibody therapy can prevent severe SARS-CoV-2 infection (COVID-19). However, the effectiveness of COVID-19 convalescent plasma (CCP) therapy in treating severe COVID-19 remains inconclusive. To test a hypothesis that some CCP units are associated with a coagulopathy hazard in severe disease that offsets its benefits, we tracked 304 CCP units administered to 414 hospitalized COVID-19 patients to assess their association with the onset of unfavorable post-transfusion D-dimer trends. CCP recipients with increasing or persistently elevated D-dimer trajectories after transfusion experienced higher mortality than those whose D-dimer levels were persistently low or decreasing after transfusion. Within the CCP donor-recipient network, recipients with increasing or persistently high D-dimer trajectories were skewed toward association with a minority of CCP units. In in vitro assays, CCP from "higher-risk" units had higher cross-reactivity with the spike protein of human seasonal betacoronavirus OC43. "Higher-risk" CCP units also mediated greater Fcγ receptor IIa signaling against cells expressing SARS-CoV-2 spike compared with "lower-risk" units. This study finds that post-transfusion activation of coagulation pathways during severe COVID-19 is associated with specific CCP antibody profiles and supports a potential mechanism of immune complex–activated coagulopathy.
ATGL links insulin dysregulation to insulin resistance in adolescents with obesity and hepatosteatosis
Authors: Aaron L. Slusher, Nicola Santoro, Alla Vash-Margita, Alfonso Galderisi, Pamela Hu, Fuyuze Tokoglu, Zhongyao Li, Elena Tarabra, Jordan Strober, Daniel F. Vatner, Gerald I. Shulman, Sonia Caprio
Journal: Journal of Clinical Investigation (2025)

BACKGROUND. This study examined the underlying cellular mechanisms associated with insulin resistance (IR) and metabolic disease risk within subcutaneous adipose tissue (SAT) in youth with obesity and IR compared with those without IR.
Extracranial arteriovenous malformations: towards etiology-based therapeutic management
Authors: Julien Coulie, Emmanuel Seront, Miikka Vikkula, Laurence M. Boon
Journal: Journal of Clinical Investigation (2025)

Anomalies during angiogenesis can initiate the formation of arteriovenous malformations (AVMs), characterized by aberrant connections between arteries and veins and fast lesional blood flow. These anomalies can manifest anywhere in the body, including the brain, and they typically appear at birth and evolve alongside growth of the individual. Depending on their location and size, AVMs can induce progressive deformation, chronic pain, functional impairment, and ulceration and pose life-threatening risks such as hemorrhage and organ dysfunction. The primary treatment modalities entail surgical intervention or embolization followed by surgery. However, these approaches are often challenging and seldom offer definitive resolution. In addition, inadequately performed surgery may trigger angiogenic rebound, fostering AVM recurrence. Advancements in comprehending the molecular pathways underlying AVMs have sparked interest in repurposing targeted therapies initially devised for cancer treatment. The first results are promising, giving new hope to the patients affected with these often devastating and debilitating lesions, the management of which presents major clinical challenges.
High PRMT5 levels, maintained by KEAP1 inhibition, drive chemoresistance in high-grade serous ovarian cancer
Authors: Harun Ozturk, Fidan Seker-Polat, Neda Abbaszadeh, Yasemin Kingham, Sandra Orsulic, Mazhar Adli
Journal: Journal of Clinical Investigation (2025)

Protein arginine methyl transferases (PRMTs) are generally upregulated in cancers. However, the mechanisms leading to this upregulation and its biological consequences are poorly understood. Here, we identify PRMT5, the main symmetric arginine methyltransferase, as a critical driver of chemoresistance in high-grade serous ovarian cancer (HGSOC). PRMT5 levels and its enzymatic activity are induced in a platinum-resistant (Pt-resistant) state at the protein level. To reveal potential regulators of high PRMT5 protein levels, we optimized intracellular immunostaining conditions and performed unbiased CRISPR screening. We identified Kelch-like ECH-associated protein 1 (KEAP1) as a top-scoring negative regulator of PRMT5. Our mechanistic studies show that KEAP1 directly interacted with PRMT5, leading to its ubiquitin-dependent degradation under normal physiological conditions. At the genomic level, ChIP studies showed that elevated PRMT5 directly interacted with the promoters of stress response genes and positively regulated their transcription. Combined PRMT5 inhibition with Pt resulted in synergistic cellular cytotoxicity in vitro and reduced tumor growth in vivo in Pt-resistant patient-derived xenograft tumors. Overall, the findings from this study identify PRMT5 as a critical therapeutic target in Pt-resistant HGSOC cells and reveal the molecular mechanisms that lead to high PRMT5 levels in Pt-treated and chemo-resistant tumors.
Deep immunophenotyping reveals circulating activated lymphocytes in individuals at risk for rheumatoid arthritis
Authors: Jun Inamo, Joshua Keegan, Alec Griffith, Tusharkanti Ghosh, Alice Horisberger, Kaitlyn Howard, John F. Pulford, Ekaterina Murzin, Brandon Hancock, Salina T. Dominguez, Miranda G. Gurra, Siddarth Gurajala, Anna Helena Jonsson, Jennifer A. Seifert, Marie L. Feser, Jill M. Norris, Ye Cao, William Apruzzese, S. Louis Bridges, Vivian P. Bykerk, Susan Goodman, Laura T. Donlin, Gary S. Firestein, Joan M. Bathon, Laura B. Hughes, Andrew Filer, Costantino Pitzalis, Jennifer H. Anolik, Larry Moreland, Nir Hacohen, Joel M. Guthridge, Judith A. James, Carla M. Cuda, Harris Perlman, Michael B. Brenner, Soumya Raychaudhuri, Jeffrey A. Sparks, V. Michael Holers, Kevin D. Deane, James Lederer, Deepak A. Rao, Fan Zhang
Journal: Journal of Clinical Investigation (2025)

Rheumatoid arthritis (RA) is a systemic autoimmune disease currently with no universally highly effective prevention strategies. Identifying pathogenic immune phenotypes in at-risk populations prior to clinical onset is crucial to establishing effective prevention strategies. Here, we applied multimodal single-cell technologies (mass cytometry and CITE-Seq) to characterize the immunophenotypes in blood from at-risk individuals (ARIs) identified through the presence of serum antibodies against citrullinated protein antigens (ACPAs) and/or first-degree relative (FDR) status, as compared with patients with established RA and people in a healthy control group. We identified significant cell expansions in ARIs compared with controls, including CCR2+CD4+ T cells, T peripheral helper (Tph) cells, type 1 T helper cells, and CXCR5+CD8+ T cells. We also found that CD15+ classical monocytes were specifically expanded in ACPA-negative FDRs, and an activated PAX5lo naive B cell population was expanded in ACPA-positive FDRs. Further, we uncovered the molecular phenotype of the CCR2+CD4+ T cells, expressing high levels of Th17- and Th22-related signature transcripts including CCR6, IL23R, KLRB1, CD96, and IL22. Our integrated study provides a promising approach to identify targets to improve prevention strategy development for RA.
Activating antiviral immune responses potentiates immune checkpoint inhibition in glioblastoma models
Authors: Deepa Seetharam, Jay Chandar, Christian K. Ramsoomair, Jelisah F. Desgraves, Alexandra Alvarado Medina, Anna Jane Hudson, Ava Amidei, Jesus R. Castro, Vaidya Govindarajan, Sarah Wang, Yong Zhang, Adam M. Sonabend, Mynor J. Mendez Valdez, Dragan Maric, Vasundara Govindarajan, Sarah R. Rivas, Victor M. Lu, Ritika Tiwari, Nima Sharifi, Emmanuel Thomas, Marcus Alexander, Catherine DeMarino, Kory Johnson, Macarena I. De La Fuente, Ruham Alshiekh Nasany, Teresa Maria Rosaria Noviello, Michael E. Ivan, Ricardo J. Komotar, Antonio Iavarone, Avindra Nath, John Heiss, Michele Ceccarelli, Katherine B. Chiappinelli, Maria E. Figueroa, Defne Bayik, Ashish H. Shah
Journal: Journal of Clinical Investigation (2025)

Viral mimicry refers to the activation of innate antiviral immune responses due to the induction of endogenous retroelements (REs). Viral mimicry augments antitumor immune responses and sensitizes solid tumors to immunotherapy. Here, we found that targeting what we believe to be a novel, master epigenetic regulator, Zinc Finger Protein 638 (ZNF638), induces viral mimicry in glioblastoma (GBM) preclinical models and potentiates immune checkpoint inhibition (ICI). ZNF638 recruits the HUSH complex, which precipitates repressive H3K9me3 marks on endogenous REs. In GBM, ZNF638 is associated with marked locoregional immunosuppressive transcriptional signatures, reduced endogenous RE expression, and poor immune cell infiltration. Targeting ZNF638 decreased H3K9 trimethylation, increased REs, and activated intracellular dsRNA signaling cascades. Furthermore, ZNF638 knockdown upregulated antiviral immune programs and significantly increased PD-L1 immune checkpoint expression in diverse GBM models. Importantly, targeting ZNF638 sensitized mice to ICI in syngeneic murine orthotopic models through innate IFN signaling. This response was recapitulated in recurrent GBM (rGBM) samples with radiographic responses to checkpoint inhibition with widely increased expression of dsRNA, PD-L1, and perivascular CD8 cell infiltration, suggesting that dsRNA signaling may mediate response to immunotherapy. Finally, low ZNF638 expression was a biomarker of clinical response to ICI and improved survival in patients with rGBM and patients with melanoma. Our findings suggest that ZNF638 could serve as a target to potentiate immunotherapy in gliomas.
Epigenetic therapy sensitizes anti–PD-1 refractory head and neck cancers to immunotherapy rechallenge
Authors: Tingting Qin, Austin K. Mattox, Jean S. Campbell, Jong Chul Park, Kee-Young Shin, Shiting Li, Peter M. Sadow, William C. Faquin, Goran Micevic, Andrew J. Daniels, Robert Haddad, Christopher S. Garris, Mikael J. Pittet, Thorsten R. Mempel, Anne ONeill, Maureen A. Sartor, Sara I. Pai
Journal: Journal of Clinical Investigation (2025)

BACKGROUND. Immune checkpoint blockade (ICB) is an effective treatment in a subset of patients diagnosed with head and neck squamous cell carcinoma (HNSCC); however, the majority of patients are refractory.
Cellular and molecular features of asthma mucus plugs provide clues about their formation and persistence
Authors: Maude A. Liegeois, Aileen Hsieh, May Al-Fouadi, Annabelle R. Charbit, Chen Xi Yang, Tillie-Louise Hackett, John V. Fahy
Journal: Journal of Clinical Investigation (2025)

BACKGROUND. Mucus plugs form in acute asthma and persist in chronic disease. Although eosinophils are implicated in mechanisms of mucus pathology, many mechanistic details about mucus plug formation and persistence in asthma are unknown.
The neutrophil antigen 3a/b polymorphism in SLC44A2 unexpectedly encodes Csa/Csb red cell antigens
Authors: Romain Duval, Alissa Soudry, Jonathan De Oliveira Rios, Sarah Liane Linguet, Miguel Taillepierre, Graziella Matesic, Alexandre Raneri, Guy Laiguillon, Emilie Le Toriellec, Emilie-Fleur Gautier, Damien Vainqueur, Jérôme Babinet, Cécile Masson, jean Christophe Gelly, Caroline Le Van Kim, Marc Romana, Dawei Chen, Sentot Santoso, Berengere Koehl, Thierry Peyrard, Slim Azouzi
Journal: Blood (2025)
Therapeutic switch from plasma to recombinant ADAMTS13 for patients with congenital TTP from Japanese real-world data
Authors: Kazuya Sakai, Atsushi Hamamura, Yoshiko Yoshimura, Miyuki Abe, Yoshiyuki Ogawa, Kazuki Tanaka, Norimichi Hattori, Tazuko Tokugawa, Rie Kanai, Fumiyoshi Ikejiri, Masahiro Takeyama, Teruhisa Taoka, Naoki Fujita, Minoru Kanaya, Katsuyoshi Koh, Hiroshi Shiragami, Hidekazu Azumi, Kenki Saito, Masanori Matsumoto
Journal: Blood (2025)
Lymphoid Malignancies in patients with Shwachman-Diamond Syndrome
Authors: Helen D. Reed, Hyunwoo Do, Edie A. Weller, Marian H. Harris, Christopher R. Reilly, Harrison K. Tsai, Jason E. Farrar, Bonnie W. Lau, Lauren Pommert, Christopher J. Gamper, Ian Atkinson, Katherine Coyne, Margret Joos, Sara Katherine Loveless, Sarah K. Steltz, Leah Cheng, Maggie Malsch, Kasiani C. Myers, Akiko Shimamura
Journal: Blood (2025)
Safety and efficacy of rilzabrutinib vs placebo in adults with immune thrombocytopenia: the phase 3 LUNA3 study
Authors: David J Kuter, Waleed Ghanima, Nichola Cooper, Howard Allen Liebman, Lei Zhang, Yu Hu, Yoshitaka Miyakawa, Wojciech Homenda, Luisa Elena Elena Morales Galindo, Ana Lisa Basquiera, Chuen Wen Tan, Guray Saydam, Marie Luise Hütter-Krönke, Chatree Chai-Adisaksopha, David Gomez-Almaguer, Huy Tran, Ho-Jin Shin, Ademar Dantas da Cunha Junior, Zsolt Lazar, Cristina Pascual-Izquierdo, Ilya Kirgner, Elisa Lucchini, Ganna Kuzmina, Michael Fillitz, Sylvain Audia, Minakshi Taparia, Matias Cordoba, Remco Diab, Mengjie Yao, Imene Gouia, Michelle Lee, Ahmed Abd Almalik Daak
Journal: Blood (2025)

Rilzabrutinib is a covalent, reversible BTK inhibitor with multiple mechanisms targeting key immune thrombocytopenia (ITP) disease pathophysiology. The phase 3 LUNA3 study in previously treated adults with persistent/chronic ITP evaluated oral rilzabrutinib 400 mg bid (n=133) vs placebo (n=69) for 24 weeks. At baseline overall, median age was 47 years (range, 18-80), 63% female, 7.7 year (range, 0.3-52.2) median duration of ITP, and 28% were splenectomized. Overall (N=202), 85 (64%) rilzabrutinib and 22 (32%) placebo patients achieved platelet response (≥50×109/L or 30×109/L-&amp;lt;50×109/L and doubled from baseline) during the first 12 weeks and were eligible to complete the double-blind period. The primary endpoint durable platelet response (platelet count ≥50×109/L for ≥two-thirds of ≥8 of the last 12 of 24 weeks without rescue therapy) was observed in 31 (23%) rilzabrutinib vs 0 placebo patients (P&amp;lt;0.0001). All secondary efficacy endpoints were significantly superior for rilzabrutinib (P&amp;lt;0.05). Median time to first platelet response was 15 d in rilzabrutinib responders. Rilzabrutinib significantly reduced rescue therapy use by 52% (P=0.0007) and improved week 25 bleeding scores (P=0.0006). Improved physical fatigue was sustained from week 13 (P=0.01) through 25 (P=0.0003). Treatment-related adverse events were mainly grade 1-2. One rilzabrutinib patient with multiple risk factors had serious treatment-related grade 3 peripheral embolism (lower left leg) and another died from unrelated pneumonia. Rilzabrutinib­­ in ITP patients who failed multiple previous therapies (splenectomy, TPO-RA, rituximab and/or fostamatinib) resulted in rapid and durable platelet response, reduced rescue medication use and bleeding, significantly improved physical fatigue, and showed favorable safety. NCT04562766; EudraCT 2020-002063-60
Genetic and epigenetic mechanisms of GPRC5D loss after anti-GPRC5D CAR T-cell therapy in multiple myeloma
Authors: Sha Ma, Jieyun Xia, Miao Zhang, Wenyu Li, Meng Xiao, Yuqian Sha, Wenya Wang, Jianteng Zhou, Ying Wang, Kunming Qi, Chunling Fu, Zengtian Sun, Dian Zhou, Qian Sun, Tingting Qiu, Zhiling Yan, Feng Zhu, Wei Chen, Hai Cheng, Wei Sang, Jiang Cao, Depeng Li, Zhenyu Zhen Li, Mariateresa Fulciniti, Yao Yao, Kailin Xu, Mingshan Niu
Journal: Blood (2025)
Loss of BCL7A Permits IRF4 Transcriptional Activity and Cellular Growth in Multiple Myeloma
Authors: Chandraditya Chakraborty, Srikanth Talluri, Moritz Binder, Eugenio Morelli, Jessica Encinas Mayoral, Sanika Derebail, Anil Aktas Samur, Charles B. Epstein, Kenneth C. Anderson, Masood A Shammas, Mehmet K. Samur, Mariateresa Fulciniti, Nikhil C. Munshi
Journal: Blood (2025)
Blunted CD40-responsive enhancer activation in CREBBP-mutant lymphomas can be restored by enforced CD4 T-cell engagement
Authors: Haopeng Yang, Wenchao Zhang, Vida Ravanmehr, Guiling Cui, Kevin Bowman, Ruidong Chen, Jared Henderson, Shyanne Ruby Lockman, Estela Rojas, Ashley Lauren Wilson, Sydney Parsons, Ariel Mechaly, Leslie Regad, Ahmed Haouz, Christopher R. Flowers, Sattva S. Neelapu, Loretta J. Nastoupil, Richard Eric Davis, Qing Deng, Fernando Rodrigues Lima, Michael R Green
Journal: Blood (2025)
HLA-haploidentical stem cell transplantation for chronic granulomatous disease: an EBMT-IEWP retrospective study
Authors: Quentin Riller, Mathias M Hauri-Hohl, Su Han Lum, Jeroen Knippenberg, Tiarlan Sirait, Alexandra Laberko, Khalid Halahleh, Hasan Hashem, Musa Karakukcu, Henrik Sengeloev, Fulvio Porta, Benedicte Bruno, Marco Zecca, Serap Aksoylar, Vincent Barlogis, Catharina Schuetz, Jochen Buechner, Maura Faraci, Claudia Wehr, Wolfgang Holter, Karin M Mellgren, Franco Locatelli, Antonio Pérez-Martínez, Felipe Suarez, Despina Moshous, Andrew R Gennery, Dmitry Balashov, Michael H Albert, Mary A Slatter, Tayfun Güngör, Bénédicte Neven
Journal: Blood (2025)
Ruxolitinib combined with dexamethasone for adult patients with newly diagnosed hemophagocytic lymphohistiocytosis in China
Authors: De Zhou, Xianbo Huang, Lixia Zhu, Xuelian Hu, Xiudi Yang, Mixue Xie, Xin Huang, Fang Yu, Juying Wei, Liya Ma, Jingjing Zhu, Shuqi Zhao, Wanzhuo Xie, Hongyan Tong, Jie Jin, Xiujin Ye
Journal: Blood (2025)

Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome, and the overall survival of adult patients is poor. Ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor, has shown promise in treating HLH and exerts synergistic effects when combined with dexamethasone. Our pilot study preliminarily demonstrated that the combination of ruxolitinib and dexamethasone (the Ru-D regimen) had a high response rate and led to favorable short-term survival outcomes in adult HLH patients. In this prospective phase 2 clinical trial, we propose the Ru-D regimen as a first-line treatment for adults newly diagnosed with HLH with unknown triggers (chictr.org.cn identifier: ChiCTR2100049996). A total of 28 Chinese patients were enrolled, and the median follow-up time was 25.1 months (range, 0.87-34.0). The 2-month OS rate (the primary endpoint) was 85.7%, which exceeded our expected 2-month OS rate of 75%. The 6-month and 2-year OS rates were 67.9% (19/28) and 53.6% (15/28), respectively. The median OS of lymphoma-associated HLH (LAHS) patients was 5.8 months, and most of these patients had NK/T-cell lymphoma. In contrast, the 2-year OS rate of non-LAHS patients was 75%. The overall response rate (ORR) was 85.7% (24/28); 17.9% (5/28) of patients achieved a complete response (CR) during the Ru-D regimen. Overall, the Ru-D regimen was well tolerated in HLH patients. This study demonstrates the efficacy and safety of the Ru-D regimen in adults newly diagnosed with HLH with unknown triggers and warrants a phase 3 randomized controlled study.
Beyond genotype: challenges in predicting disease risk for carriers of biallelic perforin variants
Authors: Oliver Wegehaupt, Oleg Borisov, Elena Sieni, Florian Oyen, Jasmin Mann, Maria Luisa Coniglio, Aurora Chinnici, Francesco Pegoraro, Linda Beneforti, Kimberly C Gilmour, Despina Moshous, Geneviève de Saint Basile, Wenying Zhang, Rebecca A Marsh, Carmela De Fusco, Katharina Wustrau, Fabio Timeus, Concetta Micalizzi, Eberhard Gunsilius, Laine Hosking, Sharon Choo, Sujal Ghosh, Anna Köttgen, Kai Lehmberg, Stephan Ehl
Journal: Blood (2025)

Genetic screening for severe congenital immuno-hematological diseases offers potential for early intervention, particularly through preemptive allogeneic stem cell transplantation (HSCT). However, the clinical value of such screening depends on precise prognostic predictions based on genotype-phenotype correlations and/or functional confirmation. We investigated familial hemophagocytic lymphohistiocytosis type 2 (FHL2), caused by PRF1 variants. Specifically we evaluated the clinical significance of the frequent PRF1 A91V variant, if present in trans with a predicted loss-of-function (pLOF) PRF1 variant, defined as "disease mutation" listed in the Human Gene Mutation Database. We combined clinical and functional data from our HLH-network registry with UK Biobank data to evaluate disease penetrance and clinical outcomes. Among 52 A91V/pLOF individuals in the registry, 39 (72%) showed FHL2-related manifestations with mean onset at 20 years. Four patients had recurrent disease, 15 were transplanted, and 14 died. Among 14 A91V/pLOF individuals identified by family screening (mean 29 years), however, only one was symptomatic. Moreover, among 21 A91V/pLOF carriers identified in 200,000 UK Biobank participants, 12 with genotypes identical to symptomatic registry patients, none had developed HLH by age 73. Premature stop pLOF alleles appeared more penetrant than missense variants, but functional data including perforin expression or cytotoxicity failed to predict disease manifestation. Our combined registry and population-based approach reveals significant variability in disease penetrance and severity among PRF1 A91V/pLOF carriers, with no clear association between genotype, functional data and clinical outcomes. This complexity illustrates the challenges of genetic screening and highlights the need for careful clinical decision-making regarding preemptive HSCT in asymptomatic carriers.