Pub Date : 2024-10-23DOI: 10.1182/blood.2024025366
Rishika Prasad,Abdur Rehman,Lubna Rehman,Faezeh Darbaniyan,Viktoria Blumenberg,Maria-Luisa Schubert,Uria Mor,Eli Zamir,Sabine Schmidt,Tomo Hayase,Chang Chia-Chi,Lauren Kelley McDaniel,Ivonne Flores,Paolo Strati,Ranjit Nair,Dai Chihara,Luis E Fayad,Sairah Ahmed,Swaminathan P Iyer,Michael L Wang,Preetesh Jain,Loretta J Nastoupil,Jason R Westin,Reetakshi Arora,Joel Gordon Turner,Fareed Khawaja,Ranran Wu,Jennifer B Dennison,Meghan Menges,Melanie Hidalgo-Vargas,Kayla M Reid,Marco L Davila,Peter Dreger,Felix Korell,Anita Schmitt,Mark R Tanner,Richard E Champlin,Christopher R Flowers,Elizabeth J Shpall,Samir Hanash,Sattva S Neelapu,Michael Schmitt,Marion Subklewe,Johannes Fahrmann,Christoph Stein-Thoeringer,Eran Elinav,Michael D Jain,Eiko Hayase,Robert R Jenq,Neeraj Y Saini
Antibiotic-induced microbiome dysbiosis is widespread in oncology, adversely affecting outcomes and side effects of various cancer treatments, including immune checkpoint inhibitors and chimeric antigen receptor T (CAR-T) cell therapies. In this study, we observed that prior exposure to broad-spectrum ABX with extended anaerobic coverage like piperacillin-tazobactam and meropenem was associated with worsened anti-CD19 CAR-T therapy survival outcomes in large B-cell lymphoma patients (n=422), compared to other ABX classes. In a discovery subset of these patients (n=67), we found that the use of these ABX was in turn associated with substantial dysbiosis of gut microbiome function, resulting in significant alterations of the gut and blood metabolome, including microbial effectors such as short-chain fatty acids (SCFAs) and other anionic metabolites, findings that were largely reproduced in an external validation cohort (n=58). Broader evaluation of circulating microbial metabolites revealed reductions in indole and cresol derivatives, as well as trimethylamine N-oxide, in patients who received ABX treatment (discovery n=40, validation n=28). These findings were recapitulated in an immune-competent CAR-T mouse model, where meropenem-induced dysbiosis led to a systemic dysmetabolome and decreased murine anti-CD19 CAR-T efficacy. Furthermore, we demonstrate that SCFAs can enhance the metabolic fitness of CAR-T cells, leading to improved tumor killing capacity. Together, these results suggest that broad-spectrum ABX deplete metabolically active commensals whose metabolites are essential for enhancing CAR-T efficacy, shedding light on the intricate relationship between ABX exposure, microbiome function and their impact on CAR-T cell efficacy. This highlights the potential for modulating the microbiome to augment CAR-T immunotherapy.
{"title":"Antibiotic-induced loss of gut microbiome metabolic output correlates with clinical responses to CAR T-cell therapy.","authors":"Rishika Prasad,Abdur Rehman,Lubna Rehman,Faezeh Darbaniyan,Viktoria Blumenberg,Maria-Luisa Schubert,Uria Mor,Eli Zamir,Sabine Schmidt,Tomo Hayase,Chang Chia-Chi,Lauren Kelley McDaniel,Ivonne Flores,Paolo Strati,Ranjit Nair,Dai Chihara,Luis E Fayad,Sairah Ahmed,Swaminathan P Iyer,Michael L Wang,Preetesh Jain,Loretta J Nastoupil,Jason R Westin,Reetakshi Arora,Joel Gordon Turner,Fareed Khawaja,Ranran Wu,Jennifer B Dennison,Meghan Menges,Melanie Hidalgo-Vargas,Kayla M Reid,Marco L Davila,Peter Dreger,Felix Korell,Anita Schmitt,Mark R Tanner,Richard E Champlin,Christopher R Flowers,Elizabeth J Shpall,Samir Hanash,Sattva S Neelapu,Michael Schmitt,Marion Subklewe,Johannes Fahrmann,Christoph Stein-Thoeringer,Eran Elinav,Michael D Jain,Eiko Hayase,Robert R Jenq,Neeraj Y Saini","doi":"10.1182/blood.2024025366","DOIUrl":"https://doi.org/10.1182/blood.2024025366","url":null,"abstract":"Antibiotic-induced microbiome dysbiosis is widespread in oncology, adversely affecting outcomes and side effects of various cancer treatments, including immune checkpoint inhibitors and chimeric antigen receptor T (CAR-T) cell therapies. In this study, we observed that prior exposure to broad-spectrum ABX with extended anaerobic coverage like piperacillin-tazobactam and meropenem was associated with worsened anti-CD19 CAR-T therapy survival outcomes in large B-cell lymphoma patients (n=422), compared to other ABX classes. In a discovery subset of these patients (n=67), we found that the use of these ABX was in turn associated with substantial dysbiosis of gut microbiome function, resulting in significant alterations of the gut and blood metabolome, including microbial effectors such as short-chain fatty acids (SCFAs) and other anionic metabolites, findings that were largely reproduced in an external validation cohort (n=58). Broader evaluation of circulating microbial metabolites revealed reductions in indole and cresol derivatives, as well as trimethylamine N-oxide, in patients who received ABX treatment (discovery n=40, validation n=28). These findings were recapitulated in an immune-competent CAR-T mouse model, where meropenem-induced dysbiosis led to a systemic dysmetabolome and decreased murine anti-CD19 CAR-T efficacy. Furthermore, we demonstrate that SCFAs can enhance the metabolic fitness of CAR-T cells, leading to improved tumor killing capacity. Together, these results suggest that broad-spectrum ABX deplete metabolically active commensals whose metabolites are essential for enhancing CAR-T efficacy, shedding light on the intricate relationship between ABX exposure, microbiome function and their impact on CAR-T cell efficacy. This highlights the potential for modulating the microbiome to augment CAR-T immunotherapy.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"194 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489663","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}
Pub Date : 2024-10-22DOI: 10.1182/blood.2024024787
Tianyi Zhang,Yi-Fang Wang,Alex Montoya,Ilinca Patrascan,Nehir Nebioglu,Husayn A Pallikonda,Radina Georgieva,James Wd King,Holger B Kramer,Pavel V Shliaha,David S Rueda,Matthias Merkenschlager
The transcription factor IKZF1 is essential for B cell development, and recurrently mutated in human B-ALL. IKZF1 has been ascribed both activating and repressive functions via interactions with coactivator and corepressor complexes, but the relative abundance of IKZF1-associated coregulators and their contribution to IKZF1-mediated gene regulation are not well understood. To address this, we performed an unbiased identification of IKZF1-interacting proteins in pre-B cells and found that IKZF1 interacts overwhelmingly with corepressors and heterochromatin-associated proteins. Time-resolved analysis of transcription and chromatin state identified transcriptional repression as the immediate response to IKZF1 induction. Transcriptional repression preceded transcriptional activation by several hours, manifesting as a decrease in the fraction of transcriptional bursts at the single molecule level. Repression was accompanied by a rapid loss of chromatin accessibility and reduced levels of H3K27ac particularly at enhancers. We identified highly conserved helical motifs within the intrinsically disordered region in IKZF1 that mediate its association with the NuRD corepressor complex through critical "KRK" residues that bind the NuRD subunit RBBP4, a mechanism shared with the TFs FOG1, BCL11A, and SALL4. Functional characterization reveals this region is necessary for to the efficient silencing of target genes and antiproliferative functions of IKZF1 in B-ALL.
{"title":"Conserved helical motifs in the IKZF1 disordered region mediate NuRD interaction and transcriptional repression.","authors":"Tianyi Zhang,Yi-Fang Wang,Alex Montoya,Ilinca Patrascan,Nehir Nebioglu,Husayn A Pallikonda,Radina Georgieva,James Wd King,Holger B Kramer,Pavel V Shliaha,David S Rueda,Matthias Merkenschlager","doi":"10.1182/blood.2024024787","DOIUrl":"https://doi.org/10.1182/blood.2024024787","url":null,"abstract":"The transcription factor IKZF1 is essential for B cell development, and recurrently mutated in human B-ALL. IKZF1 has been ascribed both activating and repressive functions via interactions with coactivator and corepressor complexes, but the relative abundance of IKZF1-associated coregulators and their contribution to IKZF1-mediated gene regulation are not well understood. To address this, we performed an unbiased identification of IKZF1-interacting proteins in pre-B cells and found that IKZF1 interacts overwhelmingly with corepressors and heterochromatin-associated proteins. Time-resolved analysis of transcription and chromatin state identified transcriptional repression as the immediate response to IKZF1 induction. Transcriptional repression preceded transcriptional activation by several hours, manifesting as a decrease in the fraction of transcriptional bursts at the single molecule level. Repression was accompanied by a rapid loss of chromatin accessibility and reduced levels of H3K27ac particularly at enhancers. We identified highly conserved helical motifs within the intrinsically disordered region in IKZF1 that mediate its association with the NuRD corepressor complex through critical \"KRK\" residues that bind the NuRD subunit RBBP4, a mechanism shared with the TFs FOG1, BCL11A, and SALL4. Functional characterization reveals this region is necessary for to the efficient silencing of target genes and antiproliferative functions of IKZF1 in B-ALL.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"5 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488242","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}
Pub Date : 2024-10-22DOI: 10.1182/blood.2024026135
Ada Antypiuk,Steven Vance,Richa Sharma,Sara T Passos,Michela Asperti,Shobana Navaneethabalakrishnan,Franz Durrenberger,Vania Manolova,Francesca Vinchi
Although iron overload is a common feature in myelodysplastic syndromes (MDS), it remains unclear how iron excess is detrimental for disease pathophysiology. Taking advantage of complementary approaches, we analyzed the impact of iron overload and restriction achieved through genetic activation (FPNC326S) and pharmacologic inhibition (vamifeport) of the iron exporter ferroportin in a MDS mouse model, respectively. While FPNC326S-induced iron overload did not significantly improve the late stages of erythroid maturation, vamifeport-mediated iron restriction ameliorated anemia and red blood cell maturation in MDS mice, through the reduction of oxidative stress and apoptosis in erythroid progenitors. Iron overload aggravated and restriction alleviated ROS formation, DNA damage and cell death in hematopoietic stem and progenitor cells, resulting in altered cell survival and quality. Finally, myeloid bias, indicated by expanded bone marrow myeloid progenitors and circulating immature myeloid blasts, was exacerbated by iron excess and attenuated by iron restriction. Overall, vamifeport treatment resulted in improved anemia and significant survival increment in MDS mice. Interestingly, the combined therapy with vamifeport and the erythroid maturation agent luspatercept has superior effect in improving anemia and myeloid bias as compared to single treatments, and offers additive beneficial effects in MDS. Our results prove for the first time in a preclinical model that iron plays a pathologic role in transfusion-independent MDS. This is likely aggravated by transfusional iron overload, as suggested by observations in the FPNC326SMDS model. Ultimately, the beneficial effects of pharmacologic FPN inhibition uncovers the therapeutic potential of early prevention of iron toxicity in transfusion-independent MDS.
{"title":"Genetic iron overload aggravates and pharmacological iron restriction improves MDS pathophysiology in a preclinical study.","authors":"Ada Antypiuk,Steven Vance,Richa Sharma,Sara T Passos,Michela Asperti,Shobana Navaneethabalakrishnan,Franz Durrenberger,Vania Manolova,Francesca Vinchi","doi":"10.1182/blood.2024026135","DOIUrl":"https://doi.org/10.1182/blood.2024026135","url":null,"abstract":"Although iron overload is a common feature in myelodysplastic syndromes (MDS), it remains unclear how iron excess is detrimental for disease pathophysiology. Taking advantage of complementary approaches, we analyzed the impact of iron overload and restriction achieved through genetic activation (FPNC326S) and pharmacologic inhibition (vamifeport) of the iron exporter ferroportin in a MDS mouse model, respectively. While FPNC326S-induced iron overload did not significantly improve the late stages of erythroid maturation, vamifeport-mediated iron restriction ameliorated anemia and red blood cell maturation in MDS mice, through the reduction of oxidative stress and apoptosis in erythroid progenitors. Iron overload aggravated and restriction alleviated ROS formation, DNA damage and cell death in hematopoietic stem and progenitor cells, resulting in altered cell survival and quality. Finally, myeloid bias, indicated by expanded bone marrow myeloid progenitors and circulating immature myeloid blasts, was exacerbated by iron excess and attenuated by iron restriction. Overall, vamifeport treatment resulted in improved anemia and significant survival increment in MDS mice. Interestingly, the combined therapy with vamifeport and the erythroid maturation agent luspatercept has superior effect in improving anemia and myeloid bias as compared to single treatments, and offers additive beneficial effects in MDS. Our results prove for the first time in a preclinical model that iron plays a pathologic role in transfusion-independent MDS. This is likely aggravated by transfusional iron overload, as suggested by observations in the FPNC326SMDS model. Ultimately, the beneficial effects of pharmacologic FPN inhibition uncovers the therapeutic potential of early prevention of iron toxicity in transfusion-independent MDS.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"410 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488237","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}
Pub Date : 2024-10-22DOI: 10.1182/blood.2024025563
Anita Kumar,Jacob D Soumerai,Jeremy S Abramson,Jeffrey A Barnes,Philip C Caron,Shalini Chhabra,Maria Chabowska,Ahmet Dogan,Lorenzo Falchi,Clare Grieve,J Erika Haydu,Patrick Connor Johnson,Ashlee Joseph,Hailey Kelly,Alyssa Labarre,Jennifer K Lue,Rosalba Martignetti,Joanna Mi,Alison J Moskowitz,Colette N Owens,Sean Plummer,Madeline Puccio,Gilles A Salles,Venkatraman E Seshan,Elizabeth Simkins,Natalie Slupe,Honglei Zhang,Andrew D Zelenetz
TP53-mutant mantle cell lymphoma (MCL) is associated with poor survival outcomes with standard chemoimmunotherapy. Dual BTK and BCL2-inhibition with or without anti-CD20 monoclonal antibody therapy has shown promising activity in TP53-mutant MCL. We conducted a multi-center phase 2 study of zanubrutinib, obinutuzumab, and venetoclax (BOVen) in untreated MCL patients with TP53 mutation. Patients initially received zanubrutinib 160mg twice daily and obinutuzumab. Obinutuzumab 1000mg was given on cycle 1 day 1, 8, 15 and day 1 of cycles 2-8. After 2 cycles, venetoclax was added with weekly dose-ramp up to 400mg daily. After 24 cycles, if patients were in complete remission with undetectable minimal residual disease using an immunosequencing assay, treatment was discontinued. The primary endpoint was met if ³11 patients were progression free at 2 years. The study included 25 patients with untreated MCL with TP53 mutation. The best overall response rate was 96% (24/25) and the complete response rate was 88% (22/25). Frequency of uMRD5 and uMRD6 at cycle 13 was 95% (18/19) and 84% (16/19). With median follow up of 28.2 months, the primary endpoint was met with a 2-year progression-free survival of 72%, and the 2-year disease-specific and overall survival were 91% and 76%, respectively. Common side effects were generally low grade and included diarrhea (64%), neutropenia (32%), and infusion-related reactions (24%). BOVen was well tolerated and met its primary efficacy endpoint in TP53-mutant mantle cell lymphoma. These data support its use and further evaluation of the BOVen regimen in this high-risk population. NCT03824483.
{"title":"Zanubrutinib, Obinutuzumab, and Venetoclax for First-Line Treatment of Mantle Cell Lymphoma with a TP53 Mutation.","authors":"Anita Kumar,Jacob D Soumerai,Jeremy S Abramson,Jeffrey A Barnes,Philip C Caron,Shalini Chhabra,Maria Chabowska,Ahmet Dogan,Lorenzo Falchi,Clare Grieve,J Erika Haydu,Patrick Connor Johnson,Ashlee Joseph,Hailey Kelly,Alyssa Labarre,Jennifer K Lue,Rosalba Martignetti,Joanna Mi,Alison J Moskowitz,Colette N Owens,Sean Plummer,Madeline Puccio,Gilles A Salles,Venkatraman E Seshan,Elizabeth Simkins,Natalie Slupe,Honglei Zhang,Andrew D Zelenetz","doi":"10.1182/blood.2024025563","DOIUrl":"https://doi.org/10.1182/blood.2024025563","url":null,"abstract":"TP53-mutant mantle cell lymphoma (MCL) is associated with poor survival outcomes with standard chemoimmunotherapy. Dual BTK and BCL2-inhibition with or without anti-CD20 monoclonal antibody therapy has shown promising activity in TP53-mutant MCL. We conducted a multi-center phase 2 study of zanubrutinib, obinutuzumab, and venetoclax (BOVen) in untreated MCL patients with TP53 mutation. Patients initially received zanubrutinib 160mg twice daily and obinutuzumab. Obinutuzumab 1000mg was given on cycle 1 day 1, 8, 15 and day 1 of cycles 2-8. After 2 cycles, venetoclax was added with weekly dose-ramp up to 400mg daily. After 24 cycles, if patients were in complete remission with undetectable minimal residual disease using an immunosequencing assay, treatment was discontinued. The primary endpoint was met if ³11 patients were progression free at 2 years. The study included 25 patients with untreated MCL with TP53 mutation. The best overall response rate was 96% (24/25) and the complete response rate was 88% (22/25). Frequency of uMRD5 and uMRD6 at cycle 13 was 95% (18/19) and 84% (16/19). With median follow up of 28.2 months, the primary endpoint was met with a 2-year progression-free survival of 72%, and the 2-year disease-specific and overall survival were 91% and 76%, respectively. Common side effects were generally low grade and included diarrhea (64%), neutropenia (32%), and infusion-related reactions (24%). BOVen was well tolerated and met its primary efficacy endpoint in TP53-mutant mantle cell lymphoma. These data support its use and further evaluation of the BOVen regimen in this high-risk population. NCT03824483.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"13 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488239","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}
Pub Date : 2024-10-22DOI: 10.1182/blood.2024024769
Stefano Comazzetto,Daniel Cassidy,Andrew W DeVilbiss,Elise Jeffery,Bethany Ottesen,Amanda Reyes,Animesh Paul,Suraj Bansal,Stephanie Z Xie,Sarah Muh,Thomas Mathews,Brandon Chen,Zhiyu Zhao,Sean J Morrison
Ascorbate (vitamin C) limits hematopoietic stem cell (HSC) function and suppresses leukemia development, partly by promoting the function of the Tet2 tumor suppressor. In humans, ascorbate is obtained from the diet while in mice it is synthesized in the liver. In this study, we show that deletion of the Slc23a2 ascorbate transporter from hematopoietic cells depleted ascorbate to undetectable levels in HSCs and MPPs without altering plasma ascorbate levels. Slc23a2 deficiency increased HSC reconstituting potential and self-renewal potential upon transplantation into irradiated mice. Slc23a2 deficiency also increased the reconstituting and self-renewal potentials of multipotent hematopoietic progenitors (MPPs), conferring the ability to long-term reconstitute irradiated mice. Slc23a2-deficient HSCs and MPPs divided much less frequently than control HSCs and MPPs. Increased self-renewal and reconstituting potential were observed particularly in quiescent Slc23a2-deficient HSCs and MPPs. The effect of Slc23a2 deficiency on MPP self-renewal was not mediated by reduced Tet2 function. Ascorbate thus regulates quiescence and restricts self-renewal potential in HSCs and MPPs such that ascorbate deficiency confers MPPs with long-term self-renewal potential.
{"title":"Ascorbate deficiency increases quiescence and self-renewal in hematopoietic stem cells and multipotent progenitors.","authors":"Stefano Comazzetto,Daniel Cassidy,Andrew W DeVilbiss,Elise Jeffery,Bethany Ottesen,Amanda Reyes,Animesh Paul,Suraj Bansal,Stephanie Z Xie,Sarah Muh,Thomas Mathews,Brandon Chen,Zhiyu Zhao,Sean J Morrison","doi":"10.1182/blood.2024024769","DOIUrl":"https://doi.org/10.1182/blood.2024024769","url":null,"abstract":"Ascorbate (vitamin C) limits hematopoietic stem cell (HSC) function and suppresses leukemia development, partly by promoting the function of the Tet2 tumor suppressor. In humans, ascorbate is obtained from the diet while in mice it is synthesized in the liver. In this study, we show that deletion of the Slc23a2 ascorbate transporter from hematopoietic cells depleted ascorbate to undetectable levels in HSCs and MPPs without altering plasma ascorbate levels. Slc23a2 deficiency increased HSC reconstituting potential and self-renewal potential upon transplantation into irradiated mice. Slc23a2 deficiency also increased the reconstituting and self-renewal potentials of multipotent hematopoietic progenitors (MPPs), conferring the ability to long-term reconstitute irradiated mice. Slc23a2-deficient HSCs and MPPs divided much less frequently than control HSCs and MPPs. Increased self-renewal and reconstituting potential were observed particularly in quiescent Slc23a2-deficient HSCs and MPPs. The effect of Slc23a2 deficiency on MPP self-renewal was not mediated by reduced Tet2 function. Ascorbate thus regulates quiescence and restricts self-renewal potential in HSCs and MPPs such that ascorbate deficiency confers MPPs with long-term self-renewal potential.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"30 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488243","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}
Pub Date : 2024-10-22DOI: 10.1182/blood.2024024837
Yuchen Liu,Dominique R Bollino,Osman M Bah,Erin T Strovel,Tien Van Le,Jinoos Zarrabi,Sunita Philip,Rena G Lapidus,Maria R Baer,Sandrine Niyongere,Vu H Duong,Christine C Dougherty,Jan Hendrik Beumer,Katherine D Caprinolo,Farin Kamangar,Ashkan Emadi
Glutamine dependency has been shown to be a metabolic vulnerability in acute myeloid leukemia (AML). Prior studies using several in vivo AML models showed that depletion of plasma glutamine induced by the long-acting crisantaspase (pegcrisantaspase or PegC) was synergistic with the BCL-2 inhibitor venetoclax (Ven), resulting in significantly reduced leukemia burden and enhanced survival. Here, we report a phase 1 study (NCT04666649) of Ven and PegC combination (VenPegC) for treating adult patients with relapsed or refractory AML, including patients who had previously received Ven. The primary endpoints were incidence of regimen limiting toxicities (RLT) and maximum tolerated dose (MTD). Twenty-five patients received at least one PegC dose with Ven and 18 efficacy-evaluable patients completed at least one VenPegC cycle; 12 (67%) had previously received Ven. Hyperbilirubinemia was the RLT and occurred in 60% of patients treated with VenPegC; 20% had Grade ≥3 bilirubin elevations. MTD was determined to be Ven 400 mg daily with biweekly PegC 750 IU/m2. The most common treatment-related adverse events of any Grade in 25 patients who received VenPegC included antithrombin III decrease (52%), elevated transaminases (36-48%), fatigue (28%), and hypofibrinogenemia (24%). No thromboembolic or hemorrhagic adverse events or clinical pancreatitis were observed. The overall complete remission rate in efficacy-evaluable patients was 33%. Response correlated with alterations in proteins involved in mRNA translation. In patients with RUNX1 mutations, the composite complete rate was 100%.
{"title":"A phase 1 study of the amino acid modulator pegcrisantaspase and venetoclax for relapsed/refractory acute myeloid leukemia.","authors":"Yuchen Liu,Dominique R Bollino,Osman M Bah,Erin T Strovel,Tien Van Le,Jinoos Zarrabi,Sunita Philip,Rena G Lapidus,Maria R Baer,Sandrine Niyongere,Vu H Duong,Christine C Dougherty,Jan Hendrik Beumer,Katherine D Caprinolo,Farin Kamangar,Ashkan Emadi","doi":"10.1182/blood.2024024837","DOIUrl":"https://doi.org/10.1182/blood.2024024837","url":null,"abstract":"Glutamine dependency has been shown to be a metabolic vulnerability in acute myeloid leukemia (AML). Prior studies using several in vivo AML models showed that depletion of plasma glutamine induced by the long-acting crisantaspase (pegcrisantaspase or PegC) was synergistic with the BCL-2 inhibitor venetoclax (Ven), resulting in significantly reduced leukemia burden and enhanced survival. Here, we report a phase 1 study (NCT04666649) of Ven and PegC combination (VenPegC) for treating adult patients with relapsed or refractory AML, including patients who had previously received Ven. The primary endpoints were incidence of regimen limiting toxicities (RLT) and maximum tolerated dose (MTD). Twenty-five patients received at least one PegC dose with Ven and 18 efficacy-evaluable patients completed at least one VenPegC cycle; 12 (67%) had previously received Ven. Hyperbilirubinemia was the RLT and occurred in 60% of patients treated with VenPegC; 20% had Grade ≥3 bilirubin elevations. MTD was determined to be Ven 400 mg daily with biweekly PegC 750 IU/m2. The most common treatment-related adverse events of any Grade in 25 patients who received VenPegC included antithrombin III decrease (52%), elevated transaminases (36-48%), fatigue (28%), and hypofibrinogenemia (24%). No thromboembolic or hemorrhagic adverse events or clinical pancreatitis were observed. The overall complete remission rate in efficacy-evaluable patients was 33%. Response correlated with alterations in proteins involved in mRNA translation. In patients with RUNX1 mutations, the composite complete rate was 100%.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"2 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488261","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}
During the transition from embryonic to adult life, the sites of hematopoiesis undergo dynamic shifts across various tissues. In adults, while bone marrow becomes the primary site for definitive hematopoiesis, the establishment of the bone marrow niche for accommodating hematopoietic stem cells (HSCs) remains incompletely understood. Here, we reveal that perinatal bone marrow mesenchymal stem cells (BMSCs) exhibit highly activated insulin-like growth factor 1 receptor (IGF1R) signaling compared to adult BMSCs. Deletion of Igf1r in perinatal BMSCs hinders the transition of HSCs from the fetal liver to the bone marrow in perinatal mice and disrupts hematopoiesis in adult individuals. Conversely, the deletion of Igf1r in adult BMSCs, adipocytes, osteoblasts, or endothelial cells does not affect HSCs in the bone marrow. Mechanistically, IGF1R signaling activates the transcription factor nuclear factor of activated T cells c1 (NFATc1) in perinatal BMSCs, which upregulates CXCL12 and other niche factors for HSC retention. Overall, IGF1R signaling in perinatal BMSCs regulates the development of the bone marrow niche for hematopoiesis.
{"title":"IGF1R signaling in perinatal mesenchymal stem cells determines definitive hematopoiesis in bone marrow.","authors":"Qi Lou,Kaizheng Jiang,Xiaoqi Wang,Yuan Pan,Guo Qiu,Binghuo Wu,Lisha Yuan,Siyu Xie,Jian Chen,Quanhui Xu,Meng Zhao,Linjia Jiang","doi":"10.1182/blood.2024024258","DOIUrl":"https://doi.org/10.1182/blood.2024024258","url":null,"abstract":"During the transition from embryonic to adult life, the sites of hematopoiesis undergo dynamic shifts across various tissues. In adults, while bone marrow becomes the primary site for definitive hematopoiesis, the establishment of the bone marrow niche for accommodating hematopoietic stem cells (HSCs) remains incompletely understood. Here, we reveal that perinatal bone marrow mesenchymal stem cells (BMSCs) exhibit highly activated insulin-like growth factor 1 receptor (IGF1R) signaling compared to adult BMSCs. Deletion of Igf1r in perinatal BMSCs hinders the transition of HSCs from the fetal liver to the bone marrow in perinatal mice and disrupts hematopoiesis in adult individuals. Conversely, the deletion of Igf1r in adult BMSCs, adipocytes, osteoblasts, or endothelial cells does not affect HSCs in the bone marrow. Mechanistically, IGF1R signaling activates the transcription factor nuclear factor of activated T cells c1 (NFATc1) in perinatal BMSCs, which upregulates CXCL12 and other niche factors for HSC retention. Overall, IGF1R signaling in perinatal BMSCs regulates the development of the bone marrow niche for hematopoiesis.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"67 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488263","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}
Pub Date : 2024-10-22DOI: 10.1182/blood.2024025093
Johannes Thaler,Carla Tripisciano,Daniel Kraemmer,Chi Hau,Nazanin Samadi,Wolfram Ruf,Ingrid Pabinger,Paul Knöbl,Rienk Nieuwland,Cihan Ay
Human saliva contains extracellular vesicles (EVs). These EVs expose extrinsic tenase complexes of tissue factor (TF) and activated factor VII (FVIIa), and trigger blood coagulation. Here, we show that EVs exposing extrinsic tenase complexes are also present in saliva of persons with severe hemophilia A, i.e. persons with FVIII deficiency. Addition of these salivary EVs to autologous FVIII-deficient blood results in FXa generation, thereby compensating for the lack of FXa generation via intrinsic tenase (FVIIIa/FIXa) complexes. Consistently, in our retrospective analysis of persons with severe hemophilia A who do not perform prophylactic FVIII substitution, oropharyngeal mucosal bleedings are infrequent and self-limited. Conversely, in saliva from persons with severe FVII deficiency, in whom oropharyngeal bleedings are prevalent, functional extrinsic tenase complexes are absent, because EVs lack FVII. Saliva from persons with severe FVII deficiency is unable to restore blood coagulation, which is due to the absence of FVII in both their saliva and blood. Picomolar levels of recombinant FVIIa can restore the coagulant potential of saliva from FVII deficient persons. Taken together, our findings may explain the paucity of oropharyngeal bleedings in persons with hemophilia A as well as the occurrence of such bleedings in persons with severe FVII deficiency.
人类唾液中含有细胞外囊泡 (EV)。这些细胞外小泡暴露于组织因子（TF）和活化因子 VII（FVIIa）的细胞外tenase 复合物，并触发血液凝固。在这里，我们发现在严重血友病 A 患者（即 FVIII 缺乏症患者）的唾液中也存在暴露外在tenase 复合物的 EVs。将这些唾液 EV 添加到自体 FVIII 缺乏症患者的血液中会导致 FXa 的生成，从而弥补通过内在tenase（FVIIIa/FIXa）复合物生成 FXa 的不足。同样，在我们对未进行预防性 FVIII 替代的重度 A 型血友病患者进行的回顾性分析中，口咽粘膜出血并不常见，而且是自限性的。相反，在严重 FVII 缺乏症患者的唾液中，由于 EVs 缺乏 FVII，口咽出血很常见，因此不存在功能性腱膜外酶复合物。严重 FVII 缺乏症患者的唾液无法恢复血液凝固，这是因为他们的唾液和血液中都缺乏 FVII。微摩尔水平的重组 FVIIa 可以恢复 FVII 缺乏者唾液的凝血潜能。综上所述，我们的研究结果可以解释为什么 A 型血友病患者很少发生口咽出血，以及为什么严重 FVII 缺乏症患者会发生口咽出血。
{"title":"Saliva from persons with hemophilia A triggers coagulation via extrinsic tenase complexes.","authors":"Johannes Thaler,Carla Tripisciano,Daniel Kraemmer,Chi Hau,Nazanin Samadi,Wolfram Ruf,Ingrid Pabinger,Paul Knöbl,Rienk Nieuwland,Cihan Ay","doi":"10.1182/blood.2024025093","DOIUrl":"https://doi.org/10.1182/blood.2024025093","url":null,"abstract":"Human saliva contains extracellular vesicles (EVs). These EVs expose extrinsic tenase complexes of tissue factor (TF) and activated factor VII (FVIIa), and trigger blood coagulation. Here, we show that EVs exposing extrinsic tenase complexes are also present in saliva of persons with severe hemophilia A, i.e. persons with FVIII deficiency. Addition of these salivary EVs to autologous FVIII-deficient blood results in FXa generation, thereby compensating for the lack of FXa generation via intrinsic tenase (FVIIIa/FIXa) complexes. Consistently, in our retrospective analysis of persons with severe hemophilia A who do not perform prophylactic FVIII substitution, oropharyngeal mucosal bleedings are infrequent and self-limited. Conversely, in saliva from persons with severe FVII deficiency, in whom oropharyngeal bleedings are prevalent, functional extrinsic tenase complexes are absent, because EVs lack FVII. Saliva from persons with severe FVII deficiency is unable to restore blood coagulation, which is due to the absence of FVII in both their saliva and blood. Picomolar levels of recombinant FVIIa can restore the coagulant potential of saliva from FVII deficient persons. Taken together, our findings may explain the paucity of oropharyngeal bleedings in persons with hemophilia A as well as the occurrence of such bleedings in persons with severe FVII deficiency.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"1 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488241","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}
Pub Date : 2024-10-22DOI: 10.1182/blood.2024025415
Alissa Visram,Dirk Larson,Aaron D Norman,Angela Dispenzieri,David L Murray,Robert A Kyle,S Vincent Rajkumar,Susan L Slager,Shaji K Kumar,Celine M Vachon
Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic pre-malignant disorder. The current standard of care is not to screen for MGUS, so it is often incidentally diagnosed in the clinic. It is unknown whether the outcomes of screened versus clinically detected MGUS differ. We compared the progression risk between screened versus clinical MGUS cohorts and assessed whether the MGUS detection method impacted risk prediction of established clinical factors (score). We included 379 screened MGUS from the Olmsted County population based study and 1384 MGUS patients diagnosed during routine clinical evaluation at Mayo Clinic. Median follow-up time for the screened versus clinical cohort was 26.6 and 40.1 years, respectively. Accounting for death as a competing risk, the cumulative incidence of progression at 25 years was similar in the screened (11.1% [95% CI 8.3-14.8]) versus clinical (10.1% [95% CI 8.6-11.8%]) MGUS cohorts, even when stratified by sex, age, or the baseline MGUS risk score. Overall, 0.9 (95% CI 0.6-1.2) screened versus 1.0 (95% CI 0.9-1.2) clinically detected MGUS patients experienced disease progression for every 100 person years of follow-up. MGUS detection method did not modify the association between MGUS risk score and progression risk (pinteraction=0.217) and did not add to known risk factors for progression (likelihood ratio test, p=0.839). Here we show that progression risk among patients with screened versus clinically detected heavy-chain MGUS was similar. Future studies are needed to assess if tailored follow-up of screened MGUS patients affects clinical outcomes.
{"title":"Comparison of progression risk of monoclonal gammopathy of undetermined significance by method of detection.","authors":"Alissa Visram,Dirk Larson,Aaron D Norman,Angela Dispenzieri,David L Murray,Robert A Kyle,S Vincent Rajkumar,Susan L Slager,Shaji K Kumar,Celine M Vachon","doi":"10.1182/blood.2024025415","DOIUrl":"https://doi.org/10.1182/blood.2024025415","url":null,"abstract":"Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic pre-malignant disorder. The current standard of care is not to screen for MGUS, so it is often incidentally diagnosed in the clinic. It is unknown whether the outcomes of screened versus clinically detected MGUS differ. We compared the progression risk between screened versus clinical MGUS cohorts and assessed whether the MGUS detection method impacted risk prediction of established clinical factors (score). We included 379 screened MGUS from the Olmsted County population based study and 1384 MGUS patients diagnosed during routine clinical evaluation at Mayo Clinic. Median follow-up time for the screened versus clinical cohort was 26.6 and 40.1 years, respectively. Accounting for death as a competing risk, the cumulative incidence of progression at 25 years was similar in the screened (11.1% [95% CI 8.3-14.8]) versus clinical (10.1% [95% CI 8.6-11.8%]) MGUS cohorts, even when stratified by sex, age, or the baseline MGUS risk score. Overall, 0.9 (95% CI 0.6-1.2) screened versus 1.0 (95% CI 0.9-1.2) clinically detected MGUS patients experienced disease progression for every 100 person years of follow-up. MGUS detection method did not modify the association between MGUS risk score and progression risk (pinteraction=0.217) and did not add to known risk factors for progression (likelihood ratio test, p=0.839). Here we show that progression risk among patients with screened versus clinically detected heavy-chain MGUS was similar. Future studies are needed to assess if tailored follow-up of screened MGUS patients affects clinical outcomes.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"3 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488238","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}
Pub Date : 2024-10-22DOI: 10.1182/blood.2024024795
Allison L Fisher,Sydney Phillips,Chia-Yu Wang,Joao A Paulo,Xia Xiao,Yang Xu,Gillian A Moschetta,Yongqiang Xue,Joseph D Mancias,Jodie L Babitt
The liver hormone hepcidin regulates systemic iron homeostasis to provide enough iron for vital processes while limiting toxicity. Hepcidin acts by degrading its receptor ferroportin (encoded by Slc40a1) to decrease iron export to plasma. Iron controls hepcidin production in part by inducing liver endothelial cells (LECs) to produce bone morphogenetic proteins (BMPs), which activate hepcidin transcription in hepatocytes. Here, we used in vitro and in vivo models to investigate whether ferroportin contributes to LEC intracellular iron content to modulate BMP expression and thereby hepcidin. Quantitative proteomics of LECs from mice fed different iron diets demonstrated an inverse relationship between dietary iron and endothelial ferroportin expression. Slc40a1 knockdown primary mouse LECs and endothelial Slc40a1 knockout mice exhibited increased LEC iron and BMP ligand expression. Endothelial Slc40a1 knockout mice also exhibited altered systemic iron homeostasis with decreased serum and total liver iron but preserved erythropoiesis. Although endothelial Slc40a1 knockout mice had similar hepcidin expression as control mice, hepcidin levels were inappropriately high relative to iron levels. Moreover, when iron levels were equalized with iron treatment, hepcidin levels were higher in endothelial Slc40a1 knockout mice than controls. Finally, LEC ferroportin levels were inversely correlated with hepcidin levels in multiple mouse models, and treatment of hepcidin-deficient mice with mini-hepcidin decreased LEC ferroportin expression. Overall, these data show that LEC ferroportin modulates LEC iron and consequently BMP expression to influence hepcidin production. Furthermore, LEC ferroportin expression is regulated by hepcidin, demonstrating bidirectional communication between LECs and hepatocytes to orchestrate systemic iron homeostasis.
{"title":"The hepcidin-ferroportin axis modulates liver endothelial cell BMP expression to influence iron homeostasis in mice.","authors":"Allison L Fisher,Sydney Phillips,Chia-Yu Wang,Joao A Paulo,Xia Xiao,Yang Xu,Gillian A Moschetta,Yongqiang Xue,Joseph D Mancias,Jodie L Babitt","doi":"10.1182/blood.2024024795","DOIUrl":"https://doi.org/10.1182/blood.2024024795","url":null,"abstract":"The liver hormone hepcidin regulates systemic iron homeostasis to provide enough iron for vital processes while limiting toxicity. Hepcidin acts by degrading its receptor ferroportin (encoded by Slc40a1) to decrease iron export to plasma. Iron controls hepcidin production in part by inducing liver endothelial cells (LECs) to produce bone morphogenetic proteins (BMPs), which activate hepcidin transcription in hepatocytes. Here, we used in vitro and in vivo models to investigate whether ferroportin contributes to LEC intracellular iron content to modulate BMP expression and thereby hepcidin. Quantitative proteomics of LECs from mice fed different iron diets demonstrated an inverse relationship between dietary iron and endothelial ferroportin expression. Slc40a1 knockdown primary mouse LECs and endothelial Slc40a1 knockout mice exhibited increased LEC iron and BMP ligand expression. Endothelial Slc40a1 knockout mice also exhibited altered systemic iron homeostasis with decreased serum and total liver iron but preserved erythropoiesis. Although endothelial Slc40a1 knockout mice had similar hepcidin expression as control mice, hepcidin levels were inappropriately high relative to iron levels. Moreover, when iron levels were equalized with iron treatment, hepcidin levels were higher in endothelial Slc40a1 knockout mice than controls. Finally, LEC ferroportin levels were inversely correlated with hepcidin levels in multiple mouse models, and treatment of hepcidin-deficient mice with mini-hepcidin decreased LEC ferroportin expression. Overall, these data show that LEC ferroportin modulates LEC iron and consequently BMP expression to influence hepcidin production. Furthermore, LEC ferroportin expression is regulated by hepcidin, demonstrating bidirectional communication between LECs and hepatocytes to orchestrate systemic iron homeostasis.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"234 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488262","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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