Cecilia Bonolo de Campos, Chantal E. McCabe, Laura A. Bruins, Daniel R. O’Brien, Sochilt Brown, Renee C. Tschumper, Cristine Allmer, Yuan Xiao Zhu, Kari G. Rabe, Sameer A. Parikh, Neil E. Kay, Huihuang Yan, James R. Cerhan, John N. Allan, Richard R. Furman, J. Brice Weinberg, Danielle M. Brander, Diane F. Jelinek, Marta Chesi, Susan L. Slager, Esteban Braggio
{"title":"Genomic characterization of chronic lymphocytic leukemia in patients of African ancestry","authors":"Cecilia Bonolo de Campos, Chantal E. McCabe, Laura A. Bruins, Daniel R. O’Brien, Sochilt Brown, Renee C. Tschumper, Cristine Allmer, Yuan Xiao Zhu, Kari G. Rabe, Sameer A. Parikh, Neil E. Kay, Huihuang Yan, James R. Cerhan, John N. Allan, Richard R. Furman, J. Brice Weinberg, Danielle M. Brander, Diane F. Jelinek, Marta Chesi, Susan L. Slager, Esteban Braggio","doi":"10.1038/s41408-024-01207-3","DOIUrl":"https://doi.org/10.1038/s41408-024-01207-3","url":null,"abstract":"<p>Despite the considerable effort to characterize the genomic landscape of chronic lymphocytic leukemia (CLL), published data have been almost exclusively derived from patients of European Ancestry (EA), with significant underrepresentation of minorities, including patients of African Ancestry (AA). To begin to address this gap, we evaluated whether differences exist in the genetic and transcriptomic features of 157 AA and 440 EA individuals diagnosed with CLL. We sequenced 59 putative driver genes and found an increased frequency of high-impact mutations in AA CLL, including genes of the DNA damage repair (DDR) pathway. Telomere erosion was also increased in AA CLL, amplifying the notion of increased genomic instability in AA CLL. Furthermore, we found transcription enrichment of the Tumor Necrosis Factor-alpha (TNFα) Signaling via NF-κB pathway in AA CLL compared to EA CLL, suggesting that tumor promoting inflammation plays an important role in AA CLL. In summary, these results suggest that genomic instability and NF-kB activation is more prevalent in AA CLL than EA CLL.</p>","PeriodicalId":8989,"journal":{"name":"Blood Cancer Journal","volume":"61 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143192022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Luciano J. Costa, Eva Medvedova, Binod Dhakal, Bhagirathbhai R. Dholaria, Kelly N. Godby, Susan Bal, Gayathri Ravi, Smith Giri, Saurabh Chhabra, Rebecca Silbermann, Natalie S. Callander
{"title":"Implications of isolated MRD progression in newly diagnosed multiple myeloma treated with quadruplet therapy","authors":"Luciano J. Costa, Eva Medvedova, Binod Dhakal, Bhagirathbhai R. Dholaria, Kelly N. Godby, Susan Bal, Gayathri Ravi, Smith Giri, Saurabh Chhabra, Rebecca Silbermann, Natalie S. Callander","doi":"10.1038/s41408-025-01219-7","DOIUrl":"https://doi.org/10.1038/s41408-025-01219-7","url":null,"abstract":"","PeriodicalId":8989,"journal":{"name":"Blood Cancer Journal","volume":"11 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143192023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rodrigo Fonseca, Yuan Xiao Zhu, Laura A. Bruins, Joseph Ahmann, Cecilia de Bonolo Campos, Esteban Braggio, Xianfeng Chen, Mariano Arribas, Susie Darvish, Seth Welsh, Erin Meermeier, Kiran K. Mangalaparthi, Richard K. Kandasamy, Greg Ahmann, J. Erin Wiedmeier-Nutor, Akhilesh Pandey, Marta Chesi, P. Leif Bergsagel, Rafael Fonseca
{"title":"Exploring BCL2 regulation and upstream signaling transduction in venetoclax resistance in multiple myeloma: potential avenues for therapeutic intervention","authors":"Rodrigo Fonseca, Yuan Xiao Zhu, Laura A. Bruins, Joseph Ahmann, Cecilia de Bonolo Campos, Esteban Braggio, Xianfeng Chen, Mariano Arribas, Susie Darvish, Seth Welsh, Erin Meermeier, Kiran K. Mangalaparthi, Richard K. Kandasamy, Greg Ahmann, J. Erin Wiedmeier-Nutor, Akhilesh Pandey, Marta Chesi, P. Leif Bergsagel, Rafael Fonseca","doi":"10.1038/s41408-025-01215-x","DOIUrl":"https://doi.org/10.1038/s41408-025-01215-x","url":null,"abstract":"<p>Investigating venetoclax (VTX) resistance in multiple myeloma (MM) is crucial for the development of novel therapeutic strategies to tackle resistance. We conducted a multi-omic characterization of established VTX-resistant isogenic human myeloma cell lines (HMCL) and primary MM patient samples pre- and post-VTX treatment. Transcriptomic and proteomic analysis revealed that resistance was largely associated with BCL-2 family protein dysregulation, including upregulation of anti-apoptotic proteins such as MCL-1, BCL-XL, BCL-2, and downregulation of pro-apoptotic members. Notably, the re-introduction of BIM into resistant cells restored VTX sensitivity and synergized with MCL-1 inhibitors. Upstream signaling pathways, including growth factor receptor tyrosine kinase (RTK) and phosphoinositide-3-kinase (PI3K) were implicated in this dysregulation. Simultaneous inhibition of MCL-1, BCL-XL, and upstream PI3K, RTK (FGF, EGF, and IGF1) mediated signaling enhanced VTX sensitivity. Post-translational modifications of MCL-1, particularly its stabilization via acetylation and phosphorylation, were investigated, although their inhibition only marginally increased VTX sensitivity. Lastly, the inhibition of AURKA and mitochondrial respiration also improved VTX sensitivity in some resistant HMCLs. Our findings suggest that combining VTX with MCL-1 and BCL-XL inhibitors or PIK3/RTK inhibitors holds potential for overcoming resistance. The study illustrates the importance of understanding molecular determinants of resistance to develop tailored therapeutic strategies.</p>","PeriodicalId":8989,"journal":{"name":"Blood Cancer Journal","volume":"11 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143125399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Luspatercept for the treatment of anemia in allo-HSCT for patients with hematological diseases","authors":"Xiangke Xin, Wenli Zhang, Zhen Li, Ruirui Gui, Juan Wang, Liyun Ji, Yanli Zhang, Baijun Fang, Yongping Song, Yingling Zu, Jian Zhou","doi":"10.1038/s41408-025-01218-8","DOIUrl":"https://doi.org/10.1038/s41408-025-01218-8","url":null,"abstract":"","PeriodicalId":8989,"journal":{"name":"Blood Cancer Journal","volume":"85 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143125395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Caroline A. Coughlin, Dhanvantri Chahar, Marianna Lekakis, Abdessamad A. Youssfi, Lingxiao Li, Evan Roberts, Natalia Campos Gallego, Claude-Henry Volmar, Ola Landgren, Shaun Brothers, Anthony J. Griswold, Catalina Amador, Daniel Bilbao, Francesco Maura, Jonathan H. Schatz
{"title":"Bruton’s tyrosine kinase inhibition re-sensitizes multidrug-resistant DLBCL tumors driven by BCL10 gain-of-function mutants to venetoclax","authors":"Caroline A. Coughlin, Dhanvantri Chahar, Marianna Lekakis, Abdessamad A. Youssfi, Lingxiao Li, Evan Roberts, Natalia Campos Gallego, Claude-Henry Volmar, Ola Landgren, Shaun Brothers, Anthony J. Griswold, Catalina Amador, Daniel Bilbao, Francesco Maura, Jonathan H. Schatz","doi":"10.1038/s41408-025-01214-y","DOIUrl":"https://doi.org/10.1038/s41408-025-01214-y","url":null,"abstract":"<p>Disparate pathogenic mechanisms complicate precision-medicine efforts to treat diffuse large B-cell lymphoma (DLBCL), the most common lymphoma diagnosis. Though potentially curable with frontline combination chemoimmunotherapy, DLBCL carries persistently poor prognosis for those with relapsed or refractory (rel/ref) disease, despite recent advances in immunotherapy. Here, we build on recent findings implicating gain-of-function mutations in the BCL10 signaling protein as drivers of resistance to Bruton’s tyrosine kinase (BTK) inhibitors. We show mutant BCL10-driven DLBCL is resistant to multiple additional drug classes, demonstrating urgency to derive mechanistically rooted strategies to overcome undruggable BCL10 mutants that stabilize BTK-independent signaling filaments upstream of NF-kB activation. BCL10 mutants promote a cytokine-reinforced positive feedback loop of lymphomagenesis driving not just NF-kB but multiple additional pathways converging on diffuse activation of oncogenic transcription factors. Up-regulation of anti-apoptotic genes increases mitochondrial membrane potential, underlying multidrug resistance. Increased expression of <i>BCL2</i>, <i>BCL2L1</i> (<i>BCL-XL</i>), and <i>BCL2A1</i> (<i>BFL1</i>) drives resistance to venetoclax, but expression can be overcome by the potent non-covalent BTK inhibitor pirtobrutinib. Venetoclax plus pirtobrutinib synergized in overcoming resistance and potently killed BCL10-mutant lymphomas in vitro and in vivo. BTK therefore retains key roles protecting DLBCL from apoptosis even when downstream activation of the BCL10 signaling complex activates NF-kB independently.</p><figure></figure>","PeriodicalId":8989,"journal":{"name":"Blood Cancer Journal","volume":"122 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143077493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. L. Morales, H. Cano, B. de la Morena-Barrio, J. L. Vives-Corrons, E. J. Cuenca-Zamora, P. Garrido-Rodríguez, C. Bento, J. Pereira, J. Martínez Nieto, T. H. Chen-Liang, J. L. Fuster, S. Caracena, M. L. Lozano, R. Teruel-Montoya, J. Corral, F. Ferrer-Marín
{"title":"CALRins5-mediated clonal hematopoiesis causes severe hemolytic anemia in a female PGK1Ser320Asn carrier","authors":"M. L. Morales, H. Cano, B. de la Morena-Barrio, J. L. Vives-Corrons, E. J. Cuenca-Zamora, P. Garrido-Rodríguez, C. Bento, J. Pereira, J. Martínez Nieto, T. H. Chen-Liang, J. L. Fuster, S. Caracena, M. L. Lozano, R. Teruel-Montoya, J. Corral, F. Ferrer-Marín","doi":"10.1038/s41408-025-01216-w","DOIUrl":"https://doi.org/10.1038/s41408-025-01216-w","url":null,"abstract":"","PeriodicalId":8989,"journal":{"name":"Blood Cancer Journal","volume":"24 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143071385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Laetitia Largeaud, Vincent Fregona, Laura A Jamrog, Camille Hamelle, Stéphanie Dufrechou, Naïs Prade, Esmaa Sellam, Pauline Enfedaque, Manon Bayet, Sylvie Hébrard, Mathieu Bouttier, Christine Didier, Bastien Gerby, Eric Delabesse, Marlène Pasquet, Cyril Broccardo
{"title":"GATA2 mutated allele specific expression is associated with a hyporesponsive state of HSC in GATA2 deficiency syndrome.","authors":"Laetitia Largeaud, Vincent Fregona, Laura A Jamrog, Camille Hamelle, Stéphanie Dufrechou, Naïs Prade, Esmaa Sellam, Pauline Enfedaque, Manon Bayet, Sylvie Hébrard, Mathieu Bouttier, Christine Didier, Bastien Gerby, Eric Delabesse, Marlène Pasquet, Cyril Broccardo","doi":"10.1038/s41408-025-01213-z","DOIUrl":"10.1038/s41408-025-01213-z","url":null,"abstract":"<p><p>GATA2 germline mutations lead to a syndrome characterized by immunodeficiency, vascular disorders and myeloid malignancies. To elucidate how these mutations affect hematopoietic homeostasis, we created a knock-in mouse model expressing the recurrent Gata2 R396Q missense mutation. Employing molecular and functional approaches, we investigated the mutation's impact on hematopoiesis, revealing significant alterations in the hematopoietic stem and progenitor (HSPC) compartment in young age. These include increased LT-HSC numbers, reduced self-renewal potential, and impaired response to acute inflammatory stimuli. The mature HSPC compartment was primarily affected at the CMP sub-population level. In the mutant LT-HSC population, we identified an aberrant subpopulation strongly expressing CD150, resembling aging, but occurring prematurely. This population showed hyporesponsiveness, accumulated over time, and exhibited allele-specific expression (ASE) favoring the mutated Gata2 allele, also observed in GATA2 mutated patients. Our findings reveal the detrimental impact of a Gata2 recurrent missense mutation on the HSC compartment contributing to its functional decline. Defects in the CMP mature compartment, along with the inflammatory molecular signature, explain the loss of heterogeneity in HPC compartment observed in patients. Finally, our study provides a valuable model that recapitulates the ASE-related pathology observed in GATA2 deficiency, shedding light on the mechanisms contributing to the disease's natural progression.</p>","PeriodicalId":8989,"journal":{"name":"Blood Cancer Journal","volume":"15 1","pages":"7"},"PeriodicalIF":12.9,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11782539/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Adrian Duek, Ilona Leviatan, Osnat Jarchowsky Dolberg, Martin H. Ellis
{"title":"Fedratinib for the treatment of myelofibrosis: a critical appraisal of clinical trial and “real-world” data","authors":"Adrian Duek, Ilona Leviatan, Osnat Jarchowsky Dolberg, Martin H. Ellis","doi":"10.1038/s41408-025-01211-1","DOIUrl":"https://doi.org/10.1038/s41408-025-01211-1","url":null,"abstract":"<p>Fedratinib is a predominantly JAK2 inhibitor that has shown efficacy in untreated and ruxolitinib-exposed patients with myelofibrosis (MF). Based on randomized clinical trial data, it is approved for use in patients with International Prognostic Scoring System (IPSS) or Dynamic International Prognostic Scoring System (DIPSS) intermediate-2 or high-risk disease and is distinguished from ruxolitinib in that it can be administered without dose reduction in patients with thrombocytopenia, to a platelet count above 50,000/µL. In these trials, fedratinib achieved significant spleen volume reduction in ~30–45% of patients and improvement in total symptom scores in 35–40% with good tolerability. In contrast, recently published real-world data suggest that these responses may not be as robust outside clinical trials. In the context of routine clinical practice spleen responses are documented in only 13–68%, with varying degrees of symptom improvement. This may be due to the lack of a uniform definition of ruxolitinib failure, which may influence the timing of initiating fedratinib as a second-line treatment and result in a more prolonged exposure to ruxolitinib prior to intitaing fedratinib treatment. We suggest that given the growing number of drugs available for use in MF, recognizing the failure of first-line (and potentially subsequent) treatments is critical to allow timely transition to potentially more active agents, as highlighted by the data pertaining to fedratinib.</p>","PeriodicalId":8989,"journal":{"name":"Blood Cancer Journal","volume":"1 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142974708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nicholas Bingham, Jaynish Shah, Daniel Wong, Sueh-li Lim, Krystal Bergin, Anna Kalff, Antonia Reale, Tiffany Khong, Sridurga Mithraprabhu, Andrew Spencer
{"title":"Whole genome sequencing and the genetics of extramedullary disease in multiple myeloma","authors":"Nicholas Bingham, Jaynish Shah, Daniel Wong, Sueh-li Lim, Krystal Bergin, Anna Kalff, Antonia Reale, Tiffany Khong, Sridurga Mithraprabhu, Andrew Spencer","doi":"10.1038/s41408-024-01208-2","DOIUrl":"https://doi.org/10.1038/s41408-024-01208-2","url":null,"abstract":"","PeriodicalId":8989,"journal":{"name":"Blood Cancer Journal","volume":"26 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142967756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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