Pub Date : 2025-02-25DOI: 10.1038/s41375-025-02537-2
Nadia Gharaee, Joanna Wegrzyn-Woltosz, Jihong Jiang, Vijay Suresh Akhade, Joshua Bridgers, Ryan J. Stubbins, Devendra Hiwase, Monika M. Kutyna, Onyee Chan, Rami Komrokji, Eric Padron, Yu Deng, Gary Cole, Patricia Umlandt, Megan Fuller, Ada Kim, Aly Karsan
Myelodysplastic neoplasms (MDS) are stem cell disorders characterized by ineffective hematopoiesis and risk of transformation to acute myeloid leukemia (AML). Chromosomal alterations are frequent in MDS, with interstitial deletion of chromosome 5q (del(5q)) being the most common. Lenalidomide is the current first-line treatment for del(5q) MDS and its efficacy relies on degradation of CK1α which is encoded by the CSNK1A1 gene located in the commonly deleted region (CDR) of chromosome 5q. However, lenalidomide-resistance is common, often secondary to loss-of-function mutations in TP53 or RUNX1. The CDR in del(5q) harbors several genes, including noncoding miRNAs, the loss of which contribute to disease phenotypes. miR-143 and miR-145 are located within the del(5q) CDR, but precise understanding of their role in human hematopoiesis and in the pathogenesis of del(5q) MDS is lacking. Here we provide evidence that deficiency of miR-143 and miR-145 plays a role in clonal expansion of del(5q) MDS. We show that insulin-like growth factor 1 receptor (IGF-1R) is a direct target of both miR-143 and miR-145. Our data demonstrate that IGF-1R inhibition reduces proliferation and viability of del(5q) cells in vitro and in vivo, and that lenalidomide-resistant del(5q) MDS cells depleted of either TP53 or RUNX1 are sensitive to IGF-1R inhibition. Resistant del(5q) MDS-L cells, as well as primary MDS marrow cells, are also sensitive to targeting of IGF-1R-related dependencies in del(5q) MDS, which include the Abl and MAPK signaling pathways. This work thus provides potential new therapeutic avenues for lenalidomide-resistant del(5q) MDS.
{"title":"Haploinsufficiency of miR-143 and miR-145 reveal targetable dependencies in resistant del(5q) myelodysplastic neoplasm","authors":"Nadia Gharaee, Joanna Wegrzyn-Woltosz, Jihong Jiang, Vijay Suresh Akhade, Joshua Bridgers, Ryan J. Stubbins, Devendra Hiwase, Monika M. Kutyna, Onyee Chan, Rami Komrokji, Eric Padron, Yu Deng, Gary Cole, Patricia Umlandt, Megan Fuller, Ada Kim, Aly Karsan","doi":"10.1038/s41375-025-02537-2","DOIUrl":"https://doi.org/10.1038/s41375-025-02537-2","url":null,"abstract":"<p>Myelodysplastic neoplasms (MDS) are stem cell disorders characterized by ineffective hematopoiesis and risk of transformation to acute myeloid leukemia (AML). Chromosomal alterations are frequent in MDS, with interstitial deletion of chromosome 5q (del(5q)) being the most common. Lenalidomide is the current first-line treatment for del(5q) MDS and its efficacy relies on degradation of CK1α which is encoded by the <i>CSNK1A1</i> gene located in the commonly deleted region (CDR) of chromosome 5q. However, lenalidomide-resistance is common, often secondary to loss-of-function mutations in <i>TP53</i> or <i>RUNX1</i>. The CDR in del(5q) harbors several genes, including noncoding miRNAs, the loss of which contribute to disease phenotypes. <i>miR-143</i> and <i>miR-145</i> are located within the del(5q) CDR, but precise understanding of their role in human hematopoiesis and in the pathogenesis of del(5q) MDS is lacking. Here we provide evidence that deficiency of <i>miR-143</i> and <i>miR-145</i> plays a role in clonal expansion of del(5q) MDS. We show that insulin-like growth factor 1 receptor (IGF-1R) is a direct target of both <i>miR-143</i> and <i>miR-145</i>. Our data demonstrate that IGF-1R inhibition reduces proliferation and viability of del(5q) cells in vitro and in vivo, and that lenalidomide-resistant del(5q) MDS cells depleted of either <i>TP53</i> or <i>RUNX1</i> are sensitive to IGF-1R inhibition. Resistant del(5q) MDS-L cells, as well as primary MDS marrow cells, are also sensitive to targeting of IGF-1R-related dependencies in del(5q) MDS, which include the Abl and MAPK signaling pathways. This work thus provides potential new therapeutic avenues for lenalidomide-resistant del(5q) MDS.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"7 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143485820","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 : 2025-02-24DOI: 10.1038/s41375-025-02536-3
Valentina Giudice, Carmine Selleri
<p>Acquisition of somatic mutations in healthy human cells is ubiquitous and age-related, although can increase the risk of cancers and nonmalignant diseases, and of all-cause mortality [1]. Somatic mutagenesis leads to genetically divergent clonal populations and decreased stem cell pool diversity, a process known as clonal hematopoiesis (CH) [2]. Hematopoietic stem cells (HSCs) can acquire 20 somatic mutations/year across the whole genome and 0.1 mutations/year in protein-coding exons. If a mutations provides a selective advantage, HSCs harboring that alteration expand, a phenomenon known as clonal evolution, common with ageing [3]. Clonal evolution is defined as the selection of a particular cancer cell population from tumor heterogeneity and is considered a Darwinian-like model to explain the process by which tumor cells survive through continuous external selection pressures, such as immune surveillance [4]. Currently, the most accepted model is the branched evolution, where a common ancestor gives rise multiple co-existing clones diverging and evolving in parallel with the acquisition of additional mutations. CH is frequent with ageing, in non-hematological conditions (e.g. cardiovascular diseases), and several hematological diseases, including monoclonal gammopathy of uncertain significance. However, its clinical significance remains unclear, as mutations accumulate with age and are considered a molecular clock of both healthy and premalignant hematopoiesis [5]. CH origins and subsequent dynamics are genotype specific, as some clones could spontaneously disappear [6]. For instance, <i>DNMT3A</i>-mutant clones quickly arise during youth, while slowdown in adulthood and elderly, often replaced by <i>TET2</i>- or splicing factor–mutated CH. Clone fitness is also context dependent. Chemotherapy and radiation are major selection pressures, strongly influencing genotype-dependent clonal expansion, dominance, or attrition [7], as clonal growth is faster for <i>TP53</i>, <i>PPM1D</i>, and <i>CHEK2</i> in individuals undergoing chemo/radiotherapy [8]. Moreover, a VAF threshold of ≥2% has been proposed as cut-off for clonal evolution: when CH clones reach that value, they are more commonly linked to malignant and nonmalignant outcomes [9].</p><p>CH is an evolving concept from a strictly neoplastic to a more dynamic and evolutionary framework, where it might reflect the stem cell pool diversity in a certain moment in the bone marrow (BM), like a snapshot of <i>panta rei</i> hematopoiesis. Conventionally, clonal evolution is defined as the selection of malignant clones under continuous external pressures, eventually leading to cancer. However, with routinely use of next-generation sequencing (NGS), CH is frequently found with ageing and some chronic conditions, without accompanying with cancer disorders [10], as clonal dynamics can be influenced by DNA-damaging stimuli and stress hematopoiesis [11, 12]. Clones carrying pathogenic variants, that could
{"title":"How fast does leukemia progress?","authors":"Valentina Giudice, Carmine Selleri","doi":"10.1038/s41375-025-02536-3","DOIUrl":"https://doi.org/10.1038/s41375-025-02536-3","url":null,"abstract":"<p>Acquisition of somatic mutations in healthy human cells is ubiquitous and age-related, although can increase the risk of cancers and nonmalignant diseases, and of all-cause mortality [1]. Somatic mutagenesis leads to genetically divergent clonal populations and decreased stem cell pool diversity, a process known as clonal hematopoiesis (CH) [2]. Hematopoietic stem cells (HSCs) can acquire 20 somatic mutations/year across the whole genome and 0.1 mutations/year in protein-coding exons. If a mutations provides a selective advantage, HSCs harboring that alteration expand, a phenomenon known as clonal evolution, common with ageing [3]. Clonal evolution is defined as the selection of a particular cancer cell population from tumor heterogeneity and is considered a Darwinian-like model to explain the process by which tumor cells survive through continuous external selection pressures, such as immune surveillance [4]. Currently, the most accepted model is the branched evolution, where a common ancestor gives rise multiple co-existing clones diverging and evolving in parallel with the acquisition of additional mutations. CH is frequent with ageing, in non-hematological conditions (e.g. cardiovascular diseases), and several hematological diseases, including monoclonal gammopathy of uncertain significance. However, its clinical significance remains unclear, as mutations accumulate with age and are considered a molecular clock of both healthy and premalignant hematopoiesis [5]. CH origins and subsequent dynamics are genotype specific, as some clones could spontaneously disappear [6]. For instance, <i>DNMT3A</i>-mutant clones quickly arise during youth, while slowdown in adulthood and elderly, often replaced by <i>TET2</i>- or splicing factor–mutated CH. Clone fitness is also context dependent. Chemotherapy and radiation are major selection pressures, strongly influencing genotype-dependent clonal expansion, dominance, or attrition [7], as clonal growth is faster for <i>TP53</i>, <i>PPM1D</i>, and <i>CHEK2</i> in individuals undergoing chemo/radiotherapy [8]. Moreover, a VAF threshold of ≥2% has been proposed as cut-off for clonal evolution: when CH clones reach that value, they are more commonly linked to malignant and nonmalignant outcomes [9].</p><p>CH is an evolving concept from a strictly neoplastic to a more dynamic and evolutionary framework, where it might reflect the stem cell pool diversity in a certain moment in the bone marrow (BM), like a snapshot of <i>panta rei</i> hematopoiesis. Conventionally, clonal evolution is defined as the selection of malignant clones under continuous external pressures, eventually leading to cancer. However, with routinely use of next-generation sequencing (NGS), CH is frequently found with ageing and some chronic conditions, without accompanying with cancer disorders [10], as clonal dynamics can be influenced by DNA-damaging stimuli and stress hematopoiesis [11, 12]. Clones carrying pathogenic variants, that could ","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"30 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477505","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 : 2025-02-24DOI: 10.1038/s41375-025-02534-5
Rahul Banerjee, Amber R. Fritz, Othman S. Akhtar, Ciara L. Freeman, Andrew J. Cowan, Nina Shah, Heather J. Landau, Shaji K. Kumar, Dan T. Vogl, Yvonne A. Efebera, Philip L. McCarthy, David H. Vesole, Adam Mendizabal, Amrita Y. Krishnan, George Somlo, Edward A. Stadtmauer, Marcelo C. Pasquini
<p>International Myeloma Working Group (IMWG) response criteria for multiple myeloma (MM) currently involve a combination of blood-based, urine-based, and marrow-based assessments [1]. Unlike blood-based assays which can be obtained from a single venipuncture, urine testing in MM requires that every urinary void over a 24-h period be collected. Collecting and storing all urinary voids can be difficult for patients with underlying frailty, treatment-related neuropathy, or unreliable access to refrigeration [2, 3]. Additionally, fewer than 1% of patients with plasma cell disorders have Bence-Jones proteinuria quantifiable on urine protein electrophoresis (UPEP) in the absence of abnormalities on serum protein electrophoresis (SPEP), serum immunofixation (SIFE), or serum free light chain (SFLC) testing [4]. In the real-world setting, fewer than a third of patients with MM undergo 24-h UPEP testing at diagnosis [5]. Several post hoc analyses of Phase 3 trials have demonstrated that the prognostic impact of 24-h urine immunofixation (UIFE) on progression-free survival (PFS) is negligible compared to that of SFLC assays or bone marrow plasma cell burden [6, 7].</p><p>The broader practicality of removing urine assessments from response criteria entirely has only been investigated once to our knowledge (Table 1) [3]. Adopting urine-free criteria led to changes in response depths for only 4% of patients in this small single-center analysis; however, the impact of these changes on PFS was not evaluated. To answer this more important question, we conducted an unplanned post hoc analysis of patients with MM enrolled in the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0702 (STaMINA) trial of treatment strategies following autologous stem cell transplantation (ASCT) (clinicaltrials.gov ID: NCT01109004). This trial demonstrated no intent-to-treat differences in PFS or overall survival between standard maintenance, post-ASCT consolidation, and tandem transplantation [8]. We pooled patient data from all study arms, including patients who did not complete their planned treatment strategies. We analyzed responses at the Day +56 timepoint following ASCT (first ASCT if patients underwent tandem transplantation), which was the first timepoint for response assessments. Patients who were non-evaluable for urine-free responses (as defined below) or who had progressive disease (PD) at this initial timepoint were excluded. Response assessments relative to diagnosis were calculated as stable disease (SD), partial response (PR), very good partial response (VGPR), or complete response (CR) [1]. To simplify comparisons, minimal responses were classified as SD and stringent complete responses as CR.</p><figure><figcaption><b data-test="table-caption">Table 1 Schema of traditional versus urine-free response criteria.</b></figcaption><span>Full size table</span><svg aria-hidden="true" focusable="false" height="16" role="img" width="16"><use xlink:href="#icon-eds-
{"title":"Urine-free response criteria predict progression-free survival in multiple myeloma: a post hoc analysis of BMT CTN 0702","authors":"Rahul Banerjee, Amber R. Fritz, Othman S. Akhtar, Ciara L. Freeman, Andrew J. Cowan, Nina Shah, Heather J. Landau, Shaji K. Kumar, Dan T. Vogl, Yvonne A. Efebera, Philip L. McCarthy, David H. Vesole, Adam Mendizabal, Amrita Y. Krishnan, George Somlo, Edward A. Stadtmauer, Marcelo C. Pasquini","doi":"10.1038/s41375-025-02534-5","DOIUrl":"https://doi.org/10.1038/s41375-025-02534-5","url":null,"abstract":"<p>International Myeloma Working Group (IMWG) response criteria for multiple myeloma (MM) currently involve a combination of blood-based, urine-based, and marrow-based assessments [1]. Unlike blood-based assays which can be obtained from a single venipuncture, urine testing in MM requires that every urinary void over a 24-h period be collected. Collecting and storing all urinary voids can be difficult for patients with underlying frailty, treatment-related neuropathy, or unreliable access to refrigeration [2, 3]. Additionally, fewer than 1% of patients with plasma cell disorders have Bence-Jones proteinuria quantifiable on urine protein electrophoresis (UPEP) in the absence of abnormalities on serum protein electrophoresis (SPEP), serum immunofixation (SIFE), or serum free light chain (SFLC) testing [4]. In the real-world setting, fewer than a third of patients with MM undergo 24-h UPEP testing at diagnosis [5]. Several post hoc analyses of Phase 3 trials have demonstrated that the prognostic impact of 24-h urine immunofixation (UIFE) on progression-free survival (PFS) is negligible compared to that of SFLC assays or bone marrow plasma cell burden [6, 7].</p><p>The broader practicality of removing urine assessments from response criteria entirely has only been investigated once to our knowledge (Table 1) [3]. Adopting urine-free criteria led to changes in response depths for only 4% of patients in this small single-center analysis; however, the impact of these changes on PFS was not evaluated. To answer this more important question, we conducted an unplanned post hoc analysis of patients with MM enrolled in the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0702 (STaMINA) trial of treatment strategies following autologous stem cell transplantation (ASCT) (clinicaltrials.gov ID: NCT01109004). This trial demonstrated no intent-to-treat differences in PFS or overall survival between standard maintenance, post-ASCT consolidation, and tandem transplantation [8]. We pooled patient data from all study arms, including patients who did not complete their planned treatment strategies. We analyzed responses at the Day +56 timepoint following ASCT (first ASCT if patients underwent tandem transplantation), which was the first timepoint for response assessments. Patients who were non-evaluable for urine-free responses (as defined below) or who had progressive disease (PD) at this initial timepoint were excluded. Response assessments relative to diagnosis were calculated as stable disease (SD), partial response (PR), very good partial response (VGPR), or complete response (CR) [1]. To simplify comparisons, minimal responses were classified as SD and stringent complete responses as CR.</p><figure><figcaption><b data-test=\"table-caption\">Table 1 Schema of traditional versus urine-free response criteria.</b></figcaption><span>Full size table</span><svg aria-hidden=\"true\" focusable=\"false\" height=\"16\" role=\"img\" width=\"16\"><use xlink:href=\"#icon-eds-","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"50 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477562","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 : 2025-02-22DOI: 10.1038/s41375-025-02542-5
Jingru Huang, Jiaying Xie, Yin Wang, Mengyao Sheng, Yue Sun, Pingyue Chen, Shaoqin Rong, Dongrui Yin, Yuanxian Wang, Ping Zhu, Stefan K. Bohlander, Guo-Liang Xu, Hai Gao, Dan Zhou, Yuheng Shi
Somatic mutations in DNA methyltransferase 3 A (DNMT3A) are frequently observed in patients with hematological malignancies. Hematopoietic stem/progenitor cells (HSPCs) with mutated DNMT3A demonstrate increased self-renewal activity and skewed lineage differentiation. However, the molecular mechanisms underlying these changes remain largely unexplored. In this study, we show that Dnmt3a loss leads to the upregulation of endogenous retroviruses (ERVs) in HSPCs, subsequently activating the cGAS-STING pathway and triggering inflammatory responses in these cells. Both genetic and pharmacological inhibition of STING effectively corrects the increased self-renewal activity and differentiation skewing induced by Dnmt3a deficiency in mice. Notably, targeting STING showed inhibited acute myeloid leukemia (AML) development in a Dnmt3a-KO; Flt3-ITD AML model, comparable to AC220, an FDA-approved FLT3-ITD inhibitor. A patient-derived xenograft (PDX) model further demonstrated that targeting STING effectively alleviates the leukemic burden of DNMT3A-mutant AML. Collectively, our findings highlight a critical role for STING in hematopoietic disorders induced by DNMT3A mutations and propose STING as a potential therapeutic target for preventing the progression of DNMT3A mutation-associated leukemia.
{"title":"STING mediates increased self-renewal and lineage skewing in DNMT3A-mutated hematopoietic stem/progenitor cells","authors":"Jingru Huang, Jiaying Xie, Yin Wang, Mengyao Sheng, Yue Sun, Pingyue Chen, Shaoqin Rong, Dongrui Yin, Yuanxian Wang, Ping Zhu, Stefan K. Bohlander, Guo-Liang Xu, Hai Gao, Dan Zhou, Yuheng Shi","doi":"10.1038/s41375-025-02542-5","DOIUrl":"https://doi.org/10.1038/s41375-025-02542-5","url":null,"abstract":"<p>Somatic mutations in DNA methyltransferase 3 A (<i>DNMT3A</i>) are frequently observed in patients with hematological malignancies. Hematopoietic stem/progenitor cells (HSPCs) with mutated <i>DNMT3A</i> demonstrate increased self-renewal activity and skewed lineage differentiation. However, the molecular mechanisms underlying these changes remain largely unexplored. In this study, we show that <i>Dnmt3a</i> loss leads to the upregulation of endogenous retroviruses (ERVs) in HSPCs, subsequently activating the cGAS-STING pathway and triggering inflammatory responses in these cells. Both genetic and pharmacological inhibition of STING effectively corrects the increased self-renewal activity and differentiation skewing induced by <i>Dnmt3a</i> deficiency in mice. Notably, targeting STING showed inhibited acute myeloid leukemia (AML) development in a <i>Dnmt3a</i>-KO; Flt3-ITD AML model, comparable to AC220, an FDA-approved FLT3-ITD inhibitor. A patient-derived xenograft (PDX) model further demonstrated that targeting STING effectively alleviates the leukemic burden of <i>DNMT3A</i>-mutant AML. Collectively, our findings highlight a critical role for STING in hematopoietic disorders induced by <i>DNMT3A</i> mutations and propose STING as a potential therapeutic target for preventing the progression of <i>DNMT3A</i> mutation-associated leukemia.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"65 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143470701","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}
Leukemic stem cells (LSCs) of acute myeloid leukemia (AML) can be enriched in the CD34+CD38- fraction and reconstitute human AML in vivo. However, in acute promyelocytic leukemia (APL), which constitutes 10% of all AML cases and is driven by promyelocytic leukemia-retinoic acid receptor alpha (PML::RARα) fusion genes, the presence of LSCs has long been unidentified because of the difficulty in efficient reconstitution of human APL in vivo. Herein, we show that LSCs of the short-type isoform APL, a subtype of APL defined by different breakpoints of the PML gene, concentrate in the CD34+CD38− fraction and express T cell immunoglobulin mucin-3 (TIM-3). Short-type APL cells exhibited distinct gene expression signatures, including LSC-related genes, compared to the other types of APL. Moreover, CD34+CD38−TIM-3+ short-type APL cells efficiently reconstituted human APL in xenograft models with high penetration, whereas CD34− differentiated APL cells did not. Furthermore, CD34+CD38−TIM-3+ short-type APL cells reconstituted leukemia cells after serial transplantation. Thus, short-type APL was hierarchically organized by self-renewing APL-LSCs. The identification of LSCs in a subset of APL and establishment of an efficient patient-derived xenograft model may contribute to further understanding the APL leukemogenesis and devise individual treatments for the eradication of APL LSCs.
{"title":"Distinct leukemogenic mechanism of acute promyelocytic leukemia based on genomic structure of PML::RARα","authors":"Mariko Minami, Teppei Sakoda, Gentaro Kawano, Yu Kochi, Kensuke Sasaki, Takeshi Sugio, Fumiaki Jinnouchi, Kohta Miyawaki, Yuya Kunisaki, Koji Kato, Toshihiro Miyamoto, Koichi Akashi, Yoshikane Kikushige","doi":"10.1038/s41375-025-02530-9","DOIUrl":"https://doi.org/10.1038/s41375-025-02530-9","url":null,"abstract":"<p>Leukemic stem cells (LSCs) of acute myeloid leukemia (AML) can be enriched in the CD34<sup>+</sup>CD38<sup>-</sup> fraction and reconstitute human AML in vivo. However, in acute promyelocytic leukemia (APL), which constitutes 10% of all AML cases and is driven by promyelocytic leukemia-retinoic acid receptor alpha (<i>PML::RARα</i>) fusion genes, the presence of LSCs has long been unidentified because of the difficulty in efficient reconstitution of human APL in vivo. Herein, we show that LSCs of the short-type isoform APL, a subtype of APL defined by different breakpoints of the <i>PML</i> gene, concentrate in the CD34<sup>+</sup>CD38<sup>−</sup> fraction and express T cell immunoglobulin mucin-3 (TIM-3). Short-type APL cells exhibited distinct gene expression signatures, including LSC-related genes, compared to the other types of APL. Moreover, CD34<sup>+</sup>CD38<sup>−</sup>TIM-3<sup>+</sup> short-type APL cells efficiently reconstituted human APL in xenograft models with high penetration, whereas CD34<sup>−</sup> differentiated APL cells did not. Furthermore, CD34<sup>+</sup>CD38<sup>−</sup>TIM-3<sup>+</sup> short-type APL cells reconstituted leukemia cells after serial transplantation. Thus, short-type APL was hierarchically organized by self-renewing APL-LSCs. The identification of LSCs in a subset of APL and establishment of an efficient patient-derived xenograft model may contribute to further understanding the APL leukemogenesis and devise individual treatments for the eradication of APL LSCs.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"505 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451472","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 : 2025-02-19DOI: 10.1038/s41375-025-02538-1
Fumiya Wada, Makoto Iwasaki, Masahiro Hirayama, Koji Kawamura, Katsuji Kaida, Noriko Doki, Hirohisa Nakamae, Yuta Hasegawa, Takahiro Fukuda, Tetsuya Eto, Nobuhiro Hiramoto, Yumiko Maruyama, Koji Nagafuji, Shuichi Ota, Jun Ishikawa, Toshihiko Ando, Tatsuo Ichinohe, Yoshiko Atsuta, Hideki Nakasone, Junya Kanda
The effects of donor characteristics on outcomes after T-cell-replete (TCR) haploidentical donor peripheral blood stem cell transplantation (PBSCT) with post-transplant cyclophosphamide (PTCy) or low-dose antithymocyte globulin (ATG) remain unclear. We evaluated the impact in 1,677 patients who received a PTCy protocol (PTCy-haplo; n = 1,107) or low-dose ATG protocol (ATG-haplo; n = 570). A low CD34+ cell dose (<4 ×106/kg) was the only donor characteristic associated with worse overall survival (OS) after PTCy-haplo (adjusted hazard ratios [aHR] = 1.49, P = 0.008), whereas increasing donor age by decade (aHR = 1.12, P = 0.008) and human leukocyte antigen 2-3 antigen mismatches (aHR = 1.46, P = 0.010), compared to HLA 0-1 antigen mismatches, were associated with worse OS after ATG-haplo. Increasing donor age was associated with a high risk of grade III–IV acute GVHD both after PTCy-haplo (HR: 1.32, P = 0.009) and ATG-haplo (HR: 1.22, P = 0.006). Offspring donors had better relapse-free survival and GVHD-free relapse-free survival than sibling donors after ATG-haplo. Our data highlights the donor characteristics associated with improved transplant outcomes after TCR haploidentical donor PBSCT with PTCy or low-dose ATG.
{"title":"Donor selection in T-cell-replete haploidentical donor peripheral blood stem cell transplantation","authors":"Fumiya Wada, Makoto Iwasaki, Masahiro Hirayama, Koji Kawamura, Katsuji Kaida, Noriko Doki, Hirohisa Nakamae, Yuta Hasegawa, Takahiro Fukuda, Tetsuya Eto, Nobuhiro Hiramoto, Yumiko Maruyama, Koji Nagafuji, Shuichi Ota, Jun Ishikawa, Toshihiko Ando, Tatsuo Ichinohe, Yoshiko Atsuta, Hideki Nakasone, Junya Kanda","doi":"10.1038/s41375-025-02538-1","DOIUrl":"https://doi.org/10.1038/s41375-025-02538-1","url":null,"abstract":"<p>The effects of donor characteristics on outcomes after T-cell-replete (TCR) haploidentical donor peripheral blood stem cell transplantation (PBSCT) with post-transplant cyclophosphamide (PTCy) or low-dose antithymocyte globulin (ATG) remain unclear. We evaluated the impact in 1,677 patients who received a PTCy protocol (PTCy-haplo; <i>n</i> = 1,107) or low-dose ATG protocol (ATG-haplo; <i>n</i> = 570). A low CD34<sup>+</sup> cell dose (<4 ×10<sup>6</sup>/kg) was the only donor characteristic associated with worse overall survival (OS) after PTCy-haplo (adjusted hazard ratios [aHR] = 1.49, <i>P</i> = 0.008), whereas increasing donor age by decade (aHR = 1.12, <i>P</i> = 0.008) and human leukocyte antigen 2-3 antigen mismatches (aHR = 1.46, <i>P</i> = 0.010), compared to HLA 0-1 antigen mismatches, were associated with worse OS after ATG-haplo. Increasing donor age was associated with a high risk of grade III–IV acute GVHD both after PTCy-haplo (HR: 1.32, <i>P</i> = 0.009) and ATG-haplo (HR: 1.22, <i>P</i> = 0.006). Offspring donors had better relapse-free survival and GVHD-free relapse-free survival than sibling donors after ATG-haplo. Our data highlights the donor characteristics associated with improved transplant outcomes after TCR haploidentical donor PBSCT with PTCy or low-dose ATG.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"24 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143443167","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 : 2025-02-17DOI: 10.1038/s41375-025-02529-2
Femke M. Hormann, Sean G. Rudd
T-cell acute lymphoblastic leukemia (T-ALL) patients often have a poor 5-year event-free survival. The only T-ALL specific drug in clinical practice is nelarabine. A prodrug of the deoxyguanosine analog ara-G, nelarabine is a rationally designed agent selective for the treatment of T-cell malignancies. Originally approved for relapsed/refractory T-ALL, it is increasingly used in T-ALL therapy and is currently being evaluated in upfront treatment. Whilst the clinical use of nelarabine has been the topic of multiple review articles, a thorough overview of the preclinical data detailing the molecular underpinnings of its anti-leukemic activity is lacking, which is critical to inform mechanism-based use. Thus, in the present article we conducted a semi-systematic review of the literature and critically evaluated the preclinical knowledge on the molecular pharmacology of nelarabine. Whilst early studies identified ara-G triphosphate to be the principal active metabolite and nuclear DNA synthesis to be a key target, many fundamental questions remain that could inform upon future use of this therapy. These include the nature of nelarabine-induced DNA lesions and their repair, together with additional cellular targets of ara-G metabolites and their role in efficacy and toxicity. A critical avenue of research in need of development is investigation of nelarabine combination therapies, both in the context of current T-ALL chemotherapy regimens and with emerging anti-leukemic agents, and we highlight some areas to pursue. Altogether, we discuss what we can learn from the preclinical literature as a whole and present our view for future research regarding nelarabine treatment in T-ALL.
{"title":"Nelarabine in T-cell acute lymphoblastic leukemia: intracellular metabolism and molecular mode-of-action","authors":"Femke M. Hormann, Sean G. Rudd","doi":"10.1038/s41375-025-02529-2","DOIUrl":"10.1038/s41375-025-02529-2","url":null,"abstract":"T-cell acute lymphoblastic leukemia (T-ALL) patients often have a poor 5-year event-free survival. The only T-ALL specific drug in clinical practice is nelarabine. A prodrug of the deoxyguanosine analog ara-G, nelarabine is a rationally designed agent selective for the treatment of T-cell malignancies. Originally approved for relapsed/refractory T-ALL, it is increasingly used in T-ALL therapy and is currently being evaluated in upfront treatment. Whilst the clinical use of nelarabine has been the topic of multiple review articles, a thorough overview of the preclinical data detailing the molecular underpinnings of its anti-leukemic activity is lacking, which is critical to inform mechanism-based use. Thus, in the present article we conducted a semi-systematic review of the literature and critically evaluated the preclinical knowledge on the molecular pharmacology of nelarabine. Whilst early studies identified ara-G triphosphate to be the principal active metabolite and nuclear DNA synthesis to be a key target, many fundamental questions remain that could inform upon future use of this therapy. These include the nature of nelarabine-induced DNA lesions and their repair, together with additional cellular targets of ara-G metabolites and their role in efficacy and toxicity. A critical avenue of research in need of development is investigation of nelarabine combination therapies, both in the context of current T-ALL chemotherapy regimens and with emerging anti-leukemic agents, and we highlight some areas to pursue. Altogether, we discuss what we can learn from the preclinical literature as a whole and present our view for future research regarding nelarabine treatment in T-ALL.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 3","pages":"531-542"},"PeriodicalIF":12.8,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-025-02529-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143434912","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}
A retrospective study of extranodal natural killer/T-cell lymphoma (ENKL) patients diagnosed between 2014 and 2021 in Japan was conducted. Among 351 patients with sufficient data, 116 (33%) were in the advanced stage (5 in stage III and 111 in stage IV) at diagnosis, and were further analyzed. The median age was 60 years (range: 19–90), and 68 (59%) were male. Ninety-four (85%) of stage IV patients had two or more extranodal involvements. The most common first-line regimen was SMILE (steroid, methotrexate, ifosfamide, L-asparaginase, and etoposide; 52%). The 2-year overall survival (OS) for all patients was 38.5%, which was significantly improved after 2017 (25.2% for 2014–2017 vs. 50.7% for 2018–2021; P = 0.008). Patients treated with SMILE showed better OS than those treated with DeVIC or CHOP (2y-OS: 57.1%, 35.8%, and 0%, respectively; P < 0.001). The prognosis was significantly better in patients who received hematopoietic stem cell transplantation (HSCT) than in those who did not (2-year OS: 68.3% vs. 17.6%, P < 0.001). Multivariate analysis showed SMILE and HSCT were significant factors for OS. In conclusion, the prognosis of advanced-stage ENKL has improved in recent years. The L-asparaginase-containing chemotherapy and subsequent HSCT is considered the recommended strategy.
{"title":"Improved prognosis of advanced-stage extranodal NK/T-cell lymphoma: results of the NKEA-Next study","authors":"Ayumi Fujimoto, Kana Miyazaki, Kimikazu Yakushijin, Takahiro Fujino, Wataru Munakata, Yasuo Ejima, Dai Maruyama, Nobuko Kubota, Takeshi Maeda, Jun Takizawa, Nobuhiro Hiramoto, Masahiro Takeuchi, Rika Sakai, Noriko Fukuhara, Senzo Taguchi, Naoko Asano, Motoko Yamaguchi, Ritsuro Suzuki","doi":"10.1038/s41375-025-02527-4","DOIUrl":"https://doi.org/10.1038/s41375-025-02527-4","url":null,"abstract":"<p>A retrospective study of extranodal natural killer/T-cell lymphoma (ENKL) patients diagnosed between 2014 and 2021 in Japan was conducted. Among 351 patients with sufficient data, 116 (33%) were in the advanced stage (5 in stage III and 111 in stage IV) at diagnosis, and were further analyzed. The median age was 60 years (range: 19–90), and 68 (59%) were male. Ninety-four (85%) of stage IV patients had two or more extranodal involvements. The most common first-line regimen was SMILE (steroid, methotrexate, ifosfamide, L-asparaginase, and etoposide; 52%). The 2-year overall survival (OS) for all patients was 38.5%, which was significantly improved after 2017 (25.2% for 2014–2017 vs. 50.7% for 2018–2021; <i>P</i> = 0.008). Patients treated with SMILE showed better OS than those treated with DeVIC or CHOP (2y-OS: 57.1%, 35.8%, and 0%, respectively; <i>P</i> < 0.001). The prognosis was significantly better in patients who received hematopoietic stem cell transplantation (HSCT) than in those who did not (2-year OS: 68.3% vs. 17.6%, <i>P</i> < 0.001). Multivariate analysis showed SMILE and HSCT were significant factors for OS. In conclusion, the prognosis of advanced-stage ENKL has improved in recent years. The L-asparaginase-containing chemotherapy and subsequent HSCT is considered the recommended strategy.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"64 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143434913","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 : 2025-02-15DOI: 10.1038/s41375-025-02528-3
Sameem M. Abedin, Guru Subramanian Guru Murthy, Mehdi Hamadani, Laura C. Michaelis, Karen-Sue Carlson, Lyndsey Runaas, Katelyn Gauger, Avinash G. Desai, Mary M. Chen, Kate L. Li, Mojisola Rotibi, Umar Syed, Madhuri Vusirikala, Alexandra Harrington, Ehab L. Atallah
Lintuzumab-Ac255 is a humanized anti-CD33 antibody linked to Actinium-225 delivering high-energy alpha-particles to leukemia cells, inciting double-strand DNA breaks and cell death. This phase 1 study assessed the safety and efficacy of lintuzumab-Ac225 after CLAG-M salvage therapy in patients with relapsed/refractory acute myeloid leukemia (R/R AML). Primary objectives were determination of maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), and safety. Using a 3 + 3 dose-escalation design, 21 patients were enrolled sequentially into 4 cohorts to receive a lintuzumab-Ac225 infusion (0.25–1.0 µCi/kg) 7 ( + 2) days after CLAG-M (days 1–6); 5 additional patients received the RP2D. Of evaluable patients, 86.7% had high-risk disease. The MTD and RP2D was 0.75 µCi/kg. Common grade 3/4 adverse events were febrile neutropenia (65.4%) and decreased white blood cells (50%). The composite complete remission (CRc) rates (CR/CRi) were 56.6% overall, 50% in patients with mutated TP53, and 38.5% in prior venetoclax-treated patients. Measurable residual disease (MRD)-negativity was achieved in 8 of 12 responders. Among all patients (n = 26), estimated 2-year OS was 23.1% (95% CI, 9.4–40.3) and estimated 1-year PFS was 30.8% (95% CI, 14.6–48.5). Lintuzumab-Ac225 plus CLAG-M was well tolerated with expected, manageable toxicities, while yielding deep and meaningful responses in high-risk R/R AML patients.
{"title":"Phase 1 study of lintuzumab-Ac225 combined with CLAG-M salvage therapy in relapsed/refractory acute myeloid leukemia","authors":"Sameem M. Abedin, Guru Subramanian Guru Murthy, Mehdi Hamadani, Laura C. Michaelis, Karen-Sue Carlson, Lyndsey Runaas, Katelyn Gauger, Avinash G. Desai, Mary M. Chen, Kate L. Li, Mojisola Rotibi, Umar Syed, Madhuri Vusirikala, Alexandra Harrington, Ehab L. Atallah","doi":"10.1038/s41375-025-02528-3","DOIUrl":"https://doi.org/10.1038/s41375-025-02528-3","url":null,"abstract":"<p>Lintuzumab-Ac255 is a humanized anti-CD33 antibody linked to Actinium-225 delivering high-energy alpha-particles to leukemia cells, inciting double-strand DNA breaks and cell death. This phase 1 study assessed the safety and efficacy of lintuzumab-Ac225 after CLAG-M salvage therapy in patients with relapsed/refractory acute myeloid leukemia (R/R AML). Primary objectives were determination of maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), and safety. Using a 3 + 3 dose-escalation design, 21 patients were enrolled sequentially into 4 cohorts to receive a lintuzumab-Ac225 infusion (0.25–1.0 µCi/kg) 7 ( + 2) days after CLAG-M (days 1–6); 5 additional patients received the RP2D. Of evaluable patients, 86.7% had high-risk disease. The MTD and RP2D was 0.75 µCi/kg. Common grade 3/4 adverse events were febrile neutropenia (65.4%) and decreased white blood cells (50%). The composite complete remission (CRc) rates (CR/CRi) were 56.6% overall, 50% in patients with mutated <i>TP53</i>, and 38.5% in prior venetoclax-treated patients. Measurable residual disease (MRD)-negativity was achieved in 8 of 12 responders. Among all patients (<i>n</i> = 26), estimated 2-year OS was 23.1% (95% CI, 9.4–40.3) and estimated 1-year PFS was 30.8% (95% CI, 14.6–48.5). Lintuzumab-Ac225 plus CLAG-M was well tolerated with expected, manageable toxicities, while yielding deep and meaningful responses in high-risk R/R AML patients.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"2 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143417438","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 : 2025-02-12DOI: 10.1038/s41375-025-02520-x
Chunhua Shi, Ze Tian, Jun Yan, Mao Zhang, Pariya Sukhumalchandra, Edward Chang, Guojun Yang, Junping You, Meng Cui, Qing Shi, Celine Kerros, Anne Philips, Na Qiao, Hiroki Torikai, Sathvik Patchametla, Anna Sergeeva, Lisa St. John, Helen He, Dmitri Wiederschain, Benjamin H. Lee, Geraldine L. C. Paulus, Dongxing Zha, Jeffrey Molldrem, Gheath Alatrash
Myeloid azurophil granules provide a rich source of intracellular leukemia antigens. Cathepsin G (CG) is a serine protease that has higher expression in acute myeloid leukemia (AML) blasts in comparison to normal myeloid progenitors. Based on the unique biology of HLA-A*0201 (HLA-A2), in which presentation of leader sequence (LS)-derived peptides is favored, we focused on the LS-CG-derived peptide CG1 (FLLPTGAEA). We previously detected CG1/HLA-A2 complexes on the surface of primary HLA-A2+ AML blasts and cell lines, and immunity targeting CG1/HLA-A2 in leukemia patients. T cell receptor (TCR)-mimic (m) antibodies are immunotherapeutic antibodies that target peptide-HLA (pHLA) complexes. Here we report on the engineering, preclinical efficacy, and safety evaluation of a novel CG1/HLA-A2-targeting, T cell-engager, bispecific antibody (CG1/A2xCD3). CG1/A2xCD3 showed high binding affinity to CG1/HLA-A2 monomers, CD3-Fc fusion protein, and to AML and T cells, with potent killing of HLA-A2+ primary AML and cell lines in vitro and in vivo. This correlated with both tumor- and CG1/A2xCD3-dependent T cell activation and cytokine secretion. Lastly, CG1/A2xCD3 had no activity against normal bone marrow. Together, these results support the targeting of LS-derived peptides and the continued clinical development of CG1/A2xCD3 in the setting of AML.
{"title":"Immunotherapy targeting a leader sequence cathepsin G-derived peptide","authors":"Chunhua Shi, Ze Tian, Jun Yan, Mao Zhang, Pariya Sukhumalchandra, Edward Chang, Guojun Yang, Junping You, Meng Cui, Qing Shi, Celine Kerros, Anne Philips, Na Qiao, Hiroki Torikai, Sathvik Patchametla, Anna Sergeeva, Lisa St. John, Helen He, Dmitri Wiederschain, Benjamin H. Lee, Geraldine L. C. Paulus, Dongxing Zha, Jeffrey Molldrem, Gheath Alatrash","doi":"10.1038/s41375-025-02520-x","DOIUrl":"https://doi.org/10.1038/s41375-025-02520-x","url":null,"abstract":"<p>Myeloid azurophil granules provide a rich source of intracellular leukemia antigens. Cathepsin G (CG) is a serine protease that has higher expression in acute myeloid leukemia (AML) blasts in comparison to normal myeloid progenitors. Based on the unique biology of HLA-A*0201 (HLA-A2), in which presentation of leader sequence (LS)-derived peptides is favored, we focused on the LS-CG-derived peptide CG1 (FLLPTGAEA). We previously detected CG1/HLA-A2 complexes on the surface of primary HLA-A2<sup>+</sup> AML blasts and cell lines, and immunity targeting CG1/HLA-A2 in leukemia patients. T cell receptor (TCR)-mimic (m) antibodies are immunotherapeutic antibodies that target peptide-HLA (pHLA) complexes. Here we report on the engineering, preclinical efficacy, and safety evaluation of a novel CG1/HLA-A2-targeting, T cell-engager, bispecific antibody (CG1/A2xCD3). CG1/A2xCD3 showed high binding affinity to CG1/HLA-A2 monomers, CD3-Fc fusion protein, and to AML and T cells, with potent killing of HLA-A2+ primary AML and cell lines in vitro and in vivo. This correlated with both tumor- and CG1/A2xCD3-dependent T cell activation and cytokine secretion. Lastly, CG1/A2xCD3 had no activity against normal bone marrow. Together, these results support the targeting of LS-derived peptides and the continued clinical development of CG1/A2xCD3 in the setting of AML.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"63 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143393112","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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