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Maternal weight during pregnancy and risk of childhood acute lymphoblastic leukemia in offspring 母亲孕期体重与后代罹患儿童急性淋巴细胞白血病的风险
IF 11.4 1区 医学
Leukemia Pub Date : 2025-01-26 DOI: 10.1038/s41375-025-02517-6
Jiaye Liu, Elham Kharazmi, Qunfeng Liang, Yafei Chen, Jan Sundquist, Kristina Sundquist, Mahdi Fallah
{"title":"Maternal weight during pregnancy and risk of childhood acute lymphoblastic leukemia in offspring","authors":"Jiaye Liu, Elham Kharazmi, Qunfeng Liang, Yafei Chen, Jan Sundquist, Kristina Sundquist, Mahdi Fallah","doi":"10.1038/s41375-025-02517-6","DOIUrl":"https://doi.org/10.1038/s41375-025-02517-6","url":null,"abstract":"<p>In addition to biological factors, maternal exposures during pregnancy can contribute to leukemogenesis in offspring. We conducted a population-based cohort study in Sweden to investigate the association between risk of acute lymphoblastic leukemia (ALL) in offspring and maternal anthropometrics during pregnancy. A total of 2,961,435 live-born singletons during 1983–2018 were followed from birth to ALL diagnosis, end of age 18, or end of 2018. 1388 children were diagnosed with ALL (55.6% boys). We observed an increased risk of ALL among daughters of overweight/obese mothers in early pregnancy [Body mass index (BMI) ≥ 25 kg/m<sup>2</sup>; Standardized incidence ratio (SIR) = 1.4, 95% CI: 1.2–1.6] compared with the risk in daughters of mothers with normal BMI. This association was not found in their sons (SIR = 1.0, 95% CI: 0.9–1.1). Similar results were found for the association between ALL and maternal BMI before delivery. We did not find an association between low or high gestational weight gain (GWG) and risk of ALL (both SIRs = 1.0) in male/female offspring. These suggest that maternal overweight/obesity are important risk factors for childhood ALL in daughters, whereas GWG is not associated with risk of ALL. Further research on this mother-daughter association may shed light on a possible sex hormone/chromosome-related etiology of ALL.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"19 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143034992","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}
引用次数: 0
Phase Ib study of PRT543, an oral protein arginine methyltransferase 5 (PRMT5) inhibitor, in patients with advanced splicing factor-mutant myeloid malignancies
IF 11.4 1区 医学
Leukemia Pub Date : 2025-01-24 DOI: 10.1038/s41375-025-02515-8
Jan Philipp Bewersdorf, Xiaoli Mi, Bin Lu, Andrew Kuykendall, David Sallman, Manish Patel, Don Stevens, Alexander Philipovskiy, Grerk Sutamtewagul, Lucia Masarova, Gina Keiffer, Amit Verma, Neha Bhagwat, Min Wang, Andrew Moore, Joseph Rager, Diane Heiser, Sunhee Ro, Wan-Jen Hong, Omar Abdel-Wahab, Eytan M. Stein
{"title":"Phase Ib study of PRT543, an oral protein arginine methyltransferase 5 (PRMT5) inhibitor, in patients with advanced splicing factor-mutant myeloid malignancies","authors":"Jan Philipp Bewersdorf, Xiaoli Mi, Bin Lu, Andrew Kuykendall, David Sallman, Manish Patel, Don Stevens, Alexander Philipovskiy, Grerk Sutamtewagul, Lucia Masarova, Gina Keiffer, Amit Verma, Neha Bhagwat, Min Wang, Andrew Moore, Joseph Rager, Diane Heiser, Sunhee Ro, Wan-Jen Hong, Omar Abdel-Wahab, Eytan M. Stein","doi":"10.1038/s41375-025-02515-8","DOIUrl":"https://doi.org/10.1038/s41375-025-02515-8","url":null,"abstract":"<figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"49 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143031301","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}
引用次数: 0
Targeting LMO2-induced autocrine FLT3 signaling to overcome chemoresistance in early T-cell precursor acute lymphoblastic leukemia 靶向lmo2诱导的自分泌FLT3信号克服早期t细胞前体急性淋巴细胞白血病的化疗耐药
IF 11.4 1区 医学
Leukemia Pub Date : 2025-01-23 DOI: 10.1038/s41375-024-02491-5
Cedric S. Tremblay, Jesslyn Saw, Feng Yan, Jacqueline A. Boyle, Ovini Amarasinghe, Shokoufeh Abdollahi, Anh N. Q. Vo, Benjamin J. Shields, Chelsea Mayoh, Hannah McCalmont, Kathryn Evans, Anna Steiner, Kevin Parsons, Matthew P. McCormack, David R. Powell, Nicholas C. Wong, Stephen M. Jane, Richard B. Lock, David J. Curtis
{"title":"Targeting LMO2-induced autocrine FLT3 signaling to overcome chemoresistance in early T-cell precursor acute lymphoblastic leukemia","authors":"Cedric S. Tremblay, Jesslyn Saw, Feng Yan, Jacqueline A. Boyle, Ovini Amarasinghe, Shokoufeh Abdollahi, Anh N. Q. Vo, Benjamin J. Shields, Chelsea Mayoh, Hannah McCalmont, Kathryn Evans, Anna Steiner, Kevin Parsons, Matthew P. McCormack, David R. Powell, Nicholas C. Wong, Stephen M. Jane, Richard B. Lock, David J. Curtis","doi":"10.1038/s41375-024-02491-5","DOIUrl":"https://doi.org/10.1038/s41375-024-02491-5","url":null,"abstract":"<p>Early T-cell Precursor Acute Lymphoblastic Leukemia (ETP-ALL) is an immature subtype of T-cell acute lymphoblastic leukemia (T-ALL) commonly show deregulation of the LMO2-LYL1 stem cell transcription factors, activating mutations of cytokine receptor signaling, and poor early response to intensive chemotherapy. Previously, studies of the <i>Lmo2</i> transgenic mouse model of ETP-ALL identified a population of stem-like T-cell progenitors with long-term self-renewal capacity and intrinsic chemotherapy resistance linked to cellular quiescence. Here, analyses of <i>Lmo2</i> transgenic mice, patient-derived xenografts, and single-cell RNA-sequencing data from primary ETP-ALL identified a rare subpopulation of leukemic stem cells expressing high levels of the cytokine receptor FLT3. Despite a highly proliferative state, these FLT3-overexpressing cells had long-term self-renewal capacity and almost complete resistance to chemotherapy. Chromatin immunoprecipitation and assay for transposase-accessible chromatin sequencing demonstrated FLT3 and its ligand may be direct targets of the LMO2 stem-cell complex. Media conditioned by <i>Lmo2</i> transgenic thymocytes revealed an autocrine FLT3-dependent signaling loop that could be targeted by the FLT3 inhibitor gilteritinib. Consequently, gilteritinib impaired in vivo growth of ETP-ALL and improved the sensitivity to chemotherapy. Furthermore, gilteritinib enhanced response to the BCL2 inhibitor venetoclax, which may enable “chemo-free” treatment of ETP-ALL. Together, these data provide a cellular and molecular explanation for enhanced cytokine signaling in <i>LMO2</i>-driven ETP-ALL beyond activating mutations and a rationale for clinical trials of FLT3 inhibitors in ETP-ALL.</p><figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"84 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143020550","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}
引用次数: 0
TLE4 is a repressor of the oncogenic activity of TLX3 in T-cell acute lymphoblastic leukemia 在t细胞急性淋巴细胞白血病中,TLE4是TLX3致癌活性的抑制因子
IF 11.4 1区 医学
Leukemia Pub Date : 2025-01-21 DOI: 10.1038/s41375-025-02513-w
Lukas Lauwereins, Quentin Van Thillo, Sofie Demeyer, Nicole Mentens, Sarah Provost, Kris Jacobs, Olga Gielen, Lien Boogaerts, Charles E. de Bock, Guillaume Andrieu, Vahid Asnafi, Jan Cools, Alexandra Veloso
{"title":"TLE4 is a repressor of the oncogenic activity of TLX3 in T-cell acute lymphoblastic leukemia","authors":"Lukas Lauwereins, Quentin Van Thillo, Sofie Demeyer, Nicole Mentens, Sarah Provost, Kris Jacobs, Olga Gielen, Lien Boogaerts, Charles E. de Bock, Guillaume Andrieu, Vahid Asnafi, Jan Cools, Alexandra Veloso","doi":"10.1038/s41375-025-02513-w","DOIUrl":"https://doi.org/10.1038/s41375-025-02513-w","url":null,"abstract":"<p>T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological disease originating from the malignant transformation of T-cell progenitors, caused by the accumulation of genetic aberrations. One-fifth of T-ALL patients are characterized by ectopic expression of the homeobox transcription factor TLX3. However, the role of TLX3 in T-ALL remains elusive, partly due to the lack of suitable study models. Strikingly, this TLX3-positive subgroup has a high frequency of FLT3 mutations, predominantly FLT3-ITD, in pediatric cases. To investigate this, we generated ex vivo cultured pro-T cells driven by the co-expression of TLX3 and FLT3-ITD, which conferred IL7 independent growth. This model allowed us to confirm that TLX3 expression and FLT3 signaling cooperate to transform T-cells and induce an oncogenic context. Data from this cell model, combined with gene expression data from TLX3 positive T-ALL cases, revealed a strong downregulation of the transcriptional repressor TLE4. Furthermore, TLE4 showed to have a repressive effect on ex vivo TLX3 T-ALL cell growth, likely caused by a partial reversal of the TLX3 transcriptional profile. In conclusion, we developed a TLX3+FLT3-ITD pro-T cell model and used it to illustrate that TLX3 directly represses TLE4 expression, which is beneficial for the oncogenic function of TLX3.</p><figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"28 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142992002","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}
引用次数: 0
Prognostic impact of expression of CD2, CD25, and/or CD30 in/on mast cells in systemic mastocytosis: a registry study of the European Competence Network on Mastocytosis 系统性肥大细胞增多症中肥大细胞中CD2、CD25和/或CD30表达对预后的影响:欧洲肥大细胞增多症能力网络的一项登记研究
IF 11.4 1区 医学
Leukemia Pub Date : 2025-01-15 DOI: 10.1038/s41375-024-02504-3
Axel Rüfer, Henning Nilius, Olivier Hermine, Marek Niedoszytko, Joanne N. G. Oude Elberink, Patrizia Bonadonna, Khalid Shoumariyeh, Theo Gulen, Karin Hartmann, Vito Sabato, Irena Angelova-Fischer, Daniel Baffoe, Deborah Christen, Anna Belloni Fortina, Christine Breynaert, Knut Brockow, Nikolas von Bubnoff, Horia Bumbea, Paul van Daele, Michael Doubek, Ingunn Dybedal, Chiara Elena, Christos Fokoloros, Aleksandra Górska, Marc Heizmann, Madlen Jentzsch, Saskia Klein, Johannes Lübke, Mattias Mattsson, André Mulder, Jens Panse, Tanja Daniela Schug, Mariarita Sciumè, Alex Stefan, Marlena Sztormowska, Judit Várkonyi, Friederike Wortmann, Akif Selim Yavuz, Martina Sperr, Jason Gotlib, Andreas Reiter, Massimo Triggiani, Wolfgang R. Sperr, Peter Valent
{"title":"Prognostic impact of expression of CD2, CD25, and/or CD30 in/on mast cells in systemic mastocytosis: a registry study of the European Competence Network on Mastocytosis","authors":"Axel Rüfer, Henning Nilius, Olivier Hermine, Marek Niedoszytko, Joanne N. G. Oude Elberink, Patrizia Bonadonna, Khalid Shoumariyeh, Theo Gulen, Karin Hartmann, Vito Sabato, Irena Angelova-Fischer, Daniel Baffoe, Deborah Christen, Anna Belloni Fortina, Christine Breynaert, Knut Brockow, Nikolas von Bubnoff, Horia Bumbea, Paul van Daele, Michael Doubek, Ingunn Dybedal, Chiara Elena, Christos Fokoloros, Aleksandra Górska, Marc Heizmann, Madlen Jentzsch, Saskia Klein, Johannes Lübke, Mattias Mattsson, André Mulder, Jens Panse, Tanja Daniela Schug, Mariarita Sciumè, Alex Stefan, Marlena Sztormowska, Judit Várkonyi, Friederike Wortmann, Akif Selim Yavuz, Martina Sperr, Jason Gotlib, Andreas Reiter, Massimo Triggiani, Wolfgang R. Sperr, Peter Valent","doi":"10.1038/s41375-024-02504-3","DOIUrl":"https://doi.org/10.1038/s41375-024-02504-3","url":null,"abstract":"<p>Expression of CD2, CD25 and/or CD30 in extracutaneous mast cells (MC) is a minor diagnostic criterion for systemic mastocytosis (SM) in the classification of the World Health Organization and International Consensus Classification. So far, it remains unknown whether expression of these antigens on MC is of prognostic significance in SM. We performed a retrospective multi-center study of patients with SM using the data set of the registry of the European Competence Network on Mastocytosis, including 5034 patients with various MC disorders. The percentage of CD2<sup>-</sup>, CD25<sup>+</sup> and/or CD30<sup>+</sup> MC was considerably lower in patients with indolent SM compared to patients with advanced SM, including aggressive SM and MC leukemia. Whereas CD25 and CD30 expression in MC could not be associated with prognosis, we found that lack of CD2 expression in MC is associated with a significantly reduced overall survival (OS) in patients with SM (<i>p</i> &lt; 0.0001). Lack of CD2 was also associated with the presence of extramedullary involvement affecting the spleen, liver, and/or lymph nodes (odds ratio 2.63 compared to SM with CD2<sup>+</sup> MC). Together, lack of CD2 expression in MC is a prognostic marker and indicator of reduced OS and extramedullary disease expansion in patients with SM.</p><figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"42 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981338","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}
引用次数: 0
Daratumumab plus lenalidomide/dexamethasone in untreated multiple myeloma: analysis of key subgroups of the MAIA study 达拉单抗联合来那度胺/地塞米松治疗未经治疗的多发性骨髓瘤:MAIA研究的关键亚组分析
IF 11.4 1区 医学
Leukemia Pub Date : 2025-01-15 DOI: 10.1038/s41375-024-02506-1
Philippe Moreau, Thierry Facon, Saad Z. Usmani, Nizar Bahlis, Noopur Raje, Torben Plesner, Robert Z. Orlowski, Supratik Basu, Hareth Nahi, Cyrille Hulin, Hang Quach, Hartmut Goldschmidt, Michael O’Dwyer, Aurore Perrot, Christopher P. Venner, Katja Weisel, Mourad Tiab, Margaret Macro, Laurent Frenzel, Xavier Leleu, George Wang, Huiling Pei, Maria Krevvata, Robin Carson, Fredrik Borgsten, Shaji K. Kumar
{"title":"Daratumumab plus lenalidomide/dexamethasone in untreated multiple myeloma: analysis of key subgroups of the MAIA study","authors":"Philippe Moreau, Thierry Facon, Saad Z. Usmani, Nizar Bahlis, Noopur Raje, Torben Plesner, Robert Z. Orlowski, Supratik Basu, Hareth Nahi, Cyrille Hulin, Hang Quach, Hartmut Goldschmidt, Michael O’Dwyer, Aurore Perrot, Christopher P. Venner, Katja Weisel, Mourad Tiab, Margaret Macro, Laurent Frenzel, Xavier Leleu, George Wang, Huiling Pei, Maria Krevvata, Robin Carson, Fredrik Borgsten, Shaji K. Kumar","doi":"10.1038/s41375-024-02506-1","DOIUrl":"https://doi.org/10.1038/s41375-024-02506-1","url":null,"abstract":"<p>In the MAIA study (median follow-up, 56.2 months), daratumumab plus lenalidomide and dexamethasone (D-Rd) significantly improved progression-free survival (PFS) and overall survival versus lenalidomide and dexamethasone (Rd) alone in transplant-ineligible newly diagnosed multiple myeloma (NDMM). In this post hoc analysis of clinically important subgroups in MAIA (median follow-up, 64.5 months), transplant-ineligible patients with NDMM were randomized 1:1 to D-Rd or Rd. The primary endpoint was PFS; secondary endpoints included overall response rate (ORR) and measurable residual disease (MRD)–negativity rate (10<sup>–5</sup>). PFS favored D-Rd versus Rd in most subgroups, including patients aged ≥75 years (HR, 0.59; 95% CI, 0.44–0.79), frail patients (HR, 0.64; 95% CI, 0.48–0.85), patients with high-risk cytogenetics (HR, 0.59; 95% CI, 0.44–0.80), and patients with isolated gain(1q21) (HR, 0.36; 95% CI, 0.19–0.67). ORRs, MRD-negativity rates, and sustained (≥12 months) MRD-negativity rates were higher with D-Rd versus Rd across subgroups. In patients aged ≥75 years, rates of grade 3/4 and serious treatment-emergent adverse events (TEAEs) were similar for D-Rd and Rd, but discontinuation due to TEAEs was lower for D-Rd. Results support use of D-Rd for high-risk patients, supporting D-Rd as a standard of care for transplant-ineligible NDMM. This trial was registered at www.clinicaltrials.gov as NCT02252172.</p><figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"75 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986794","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}
引用次数: 0
Multi-omic analysis of chronic myelomonocytic leukemia monocytes reveals metabolic and immune dysregulation leading to altered macrophage polarization 慢性骨髓单核细胞白血病单核细胞的多组学分析揭示了代谢和免疫失调导致巨噬细胞极化改变
IF 11.4 1区 医学
Leukemia Pub Date : 2025-01-15 DOI: 10.1038/s41375-024-02511-4
Hasse M. Addinsell, Rachel Cant, Nathan J. Hull, Yu-Hung Wang, Tim C. P. Somervaille, Daniel H. Wiseman, Kiran Batta
{"title":"Multi-omic analysis of chronic myelomonocytic leukemia monocytes reveals metabolic and immune dysregulation leading to altered macrophage polarization","authors":"Hasse M. Addinsell, Rachel Cant, Nathan J. Hull, Yu-Hung Wang, Tim C. P. Somervaille, Daniel H. Wiseman, Kiran Batta","doi":"10.1038/s41375-024-02511-4","DOIUrl":"https://doi.org/10.1038/s41375-024-02511-4","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"30 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986793","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}
引用次数: 0
Prognostic, biological, and structural implications of FLT3-JMD point mutations in acute myeloid leukemia: an analysis of Alliance studies 急性髓性白血病FLT3-JMD点突变的预后、生物学和结构意义:联盟研究的分析
IF 11.4 1区 医学
Leukemia Pub Date : 2025-01-13 DOI: 10.1038/s41375-024-02498-y
Nadeen Anabtawi, Deedra Nicolet, Najla Alotaibi, Daelynn R. Buelow, Shelley Orwick, Thomas Gregory, Ruchika Raj, Kennedy Coleman, Jonathan E. Kolitz, Bayard L. Powell, William G. Blum, Maria R. Baer, John C. Byrd, Wendy Stock, Geoffrey L. Uy, Krzysztof Mrózek, Ann-Kathrin Eisfeld, Xiaolin Cheng, Sharyn D. Baker, James S. Blachly
{"title":"Prognostic, biological, and structural implications of FLT3-JMD point mutations in acute myeloid leukemia: an analysis of Alliance studies","authors":"Nadeen Anabtawi, Deedra Nicolet, Najla Alotaibi, Daelynn R. Buelow, Shelley Orwick, Thomas Gregory, Ruchika Raj, Kennedy Coleman, Jonathan E. Kolitz, Bayard L. Powell, William G. Blum, Maria R. Baer, John C. Byrd, Wendy Stock, Geoffrey L. Uy, Krzysztof Mrózek, Ann-Kathrin Eisfeld, Xiaolin Cheng, Sharyn D. Baker, James S. Blachly","doi":"10.1038/s41375-024-02498-y","DOIUrl":"https://doi.org/10.1038/s41375-024-02498-y","url":null,"abstract":"<p>The <i>FLT3</i> gene frequently undergoes mutations in acute myeloid leukemia (AML), with internal tandem duplications (ITD) and tyrosine kinase domain (TKD) point mutations (PMs) being most common. Recently, PMs and deletions in the <i>FLT3</i> juxtamembrane domain (JMD) have been identified, but their biological and clinical significance remains poorly understood. We analyzed 1660 patients with de novo AML and found <i>FLT3</i>-JMD mutations, mostly PMs, in 2% of the patients. Patients with <i>FLT3</i>-JMD mutations had a higher relapse rate and shorter disease-free survival than those with <i>FLT3</i>-TKD, whereas their relapse rate, disease-free and overall survival were not significantly different from those of <i>FLT3</i>-ITD-positive patients. In vitro experiments showed that <i>FLT3</i>-JMD PMs transformed hematopoietic cells and responded well to type I and II FLT3 inhibitors. Molecular dynamics simulations were used to explore the conformational changes of JMD PMs relative to wild-type FLT3. These mutations exhibited constrained domain motions with wider gate openings, potentially enhancing drug binding. Altered residue interactions and structural changes shed light on their unique functional mechanisms, with increased allosteric pathways suggesting reduced interactions with other residues. We conclude that patients with <i>FLT3</i>-JMD PMs represent uncommon but important subset with distinct molecular and biological features, and may benefit from FLT3 inhibitors.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"36 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968226","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}
引用次数: 0
A novel prognostic risk model for patients with refractory/relapsed acute myeloid leukemia receiving venetoclax plus hypomethylating agents 难治性/复发性急性髓性白血病患者接受venetoclax加低甲基化药物治疗的新预后风险模型
IF 11.4 1区 医学
Leukemia Pub Date : 2025-01-08 DOI: 10.1038/s41375-024-02501-6
Rabia Shahswar, Razif Gabdoulline, Katja Krueger, Martin Wichmann, Katharina S. Götze, Krischan Braitsch, Manja Meggendorfer, Laura Schmalbrock, Lars Bullinger, Franziska Modemann, Walter Fiedler, Juergen Krauter, Stephan Kaun, Susanne Rotermund, Andreas Voß, Yvonne Lisa Behrens, Anke Katharina Bergmann, Elisabeth Koller, Gernot Beutel, Felicitas Thol, Florian Heidel, Michael Heuser
{"title":"A novel prognostic risk model for patients with refractory/relapsed acute myeloid leukemia receiving venetoclax plus hypomethylating agents","authors":"Rabia Shahswar, Razif Gabdoulline, Katja Krueger, Martin Wichmann, Katharina S. Götze, Krischan Braitsch, Manja Meggendorfer, Laura Schmalbrock, Lars Bullinger, Franziska Modemann, Walter Fiedler, Juergen Krauter, Stephan Kaun, Susanne Rotermund, Andreas Voß, Yvonne Lisa Behrens, Anke Katharina Bergmann, Elisabeth Koller, Gernot Beutel, Felicitas Thol, Florian Heidel, Michael Heuser","doi":"10.1038/s41375-024-02501-6","DOIUrl":"https://doi.org/10.1038/s41375-024-02501-6","url":null,"abstract":"<p>Off-label hypomethylating agents and venetoclax (HMA/VEN) are often used for relapsed and refractory (R/R) AML patients. However, predictors of outcome are elusive. The objective of the current retrospective observational multicenter study of 240 adult patients (median age 68.6 years) with R/R AML was to establish a prognostic risk score. Overall response was documented in 106 (44%) patients. With a median follow-up of 31.5 months, 179 deaths were recorded. Median overall survival (mOS) was 7.9 months. In multivariate analysis of the subgroup with molecular information (<i>n</i> = 174), risk factors for inferior survival included the presence of extramedullary disease, HMA pretreatment and mutations in <i>NF1</i>, <i>PTPN11</i>, <i>FLT3</i>, and <i>TP53</i>, whereas mutated <i>SF3B1</i> was identified as favorable risk factor. These risk factors were subsequently applied to construct an HR-weighted risk model that allocated patients to one of three risk groups with significantly different survival outcomes: favorable (<i>n</i> = 46; mOS 21.4 months), intermediate (<i>n</i> = 75; mOS 7.5 months), and adverse (<i>n</i> = 53; mOS 4.6 months; <i>p</i> &lt; 0.001). The model was validated in 189 AML patients treated with HMA/VEN in first line. This clinical-molecular, 3-tiered <b>ven</b>etoclax <b>p</b>rognostic <b>r</b>isk <b>s</b>core (VEN-PRS) for HMA/VEN treatment outcomes in R/R AML patients will support the selection of appropriate treatment options in this high-risk population.</p><figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"99 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936203","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}
引用次数: 0
Modeling GATA2 deficiency in mice: the R396Q mutation disrupts normal hematopoiesis 小鼠模型GATA2缺陷:R396Q突变破坏正常造血
IF 11.4 1区 医学
Leukemia Pub Date : 2025-01-07 DOI: 10.1038/s41375-024-02508-z
Trent Hall, Rashid Mehmood, Diana Sá da Bandeira, Anitria Cotton, Jonathon Klein, Shondra M. Pruett-Miller, Shai Izraeli, Wilson K. Clements, John D. Crispino
{"title":"Modeling GATA2 deficiency in mice: the R396Q mutation disrupts normal hematopoiesis","authors":"Trent Hall, Rashid Mehmood, Diana Sá da Bandeira, Anitria Cotton, Jonathon Klein, Shondra M. Pruett-Miller, Shai Izraeli, Wilson K. Clements, John D. Crispino","doi":"10.1038/s41375-024-02508-z","DOIUrl":"https://doi.org/10.1038/s41375-024-02508-z","url":null,"abstract":"<p>GATA2 deficiency is an autosomal dominant germline disorder of immune dysfunction and bone marrow failure with a high propensity for leukemic transformation. While sequencing studies have identified several secondary mutations thought to contribute to malignancy, the mechanisms of disease progression have been difficult to identify due to a lack of disease-specific experimental models. Here, we describe a murine model of one of the most common <i>GATA2</i> mutations associated with leukemic progression in GATA2 deficiency, <i>Gata2</i><sup>R396Q/+</sup>. While mutant mice exhibit mild defects in peripheral blood, they display significant hematopoietic abnormalities in the bone marrow, including a reduction in hematopoietic stem cell (HSC) function and intrinsic biases toward specific stem cell subsets that differ from previous models of GATA2 loss. Supporting this observation, single-cell RNA sequencing of hematopoietic progenitors revealed a loss of stemness, myeloid-bias, and indications of accelerated aging. Importantly, we show that <i>Gata2</i><sup>R396Q/+</sup> exerts effects early in hematopoietic development, as mutant mice generate fewer HSCs in the aorta gonad mesonephros, and fetal liver HSCs have reduced function. This reduced and altered pool of HSCs could be potential contributors to leukemic transformation in patients, and our model provides a useful tool to study the mechanisms of malignant transformation in GATA2 deficiency.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"21 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142934497","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}
引用次数: 0
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