Pub Date : 2025-01-07DOI: 10.1038/s41375-024-02508-z
Trent Hall, Rashid Mehmood, Diana Sá da Bandeira, Anitria Cotton, Jonathon Klein, Shondra M. Pruett-Miller, Shai Izraeli, Wilson K. Clements, John D. Crispino
GATA2 deficiency is an autosomal dominant germline disorder of immune dysfunction and bone marrow failure with a high propensity for leukemic transformation. While sequencing studies have identified several secondary mutations thought to contribute to malignancy, the mechanisms of disease progression have been difficult to identify due to a lack of disease-specific experimental models. Here, we describe a murine model of one of the most common GATA2 mutations associated with leukemic progression in GATA2 deficiency, Gata2R396Q/+. While mutant mice exhibit mild defects in peripheral blood, they display significant hematopoietic abnormalities in the bone marrow, including a reduction in hematopoietic stem cell (HSC) function and intrinsic biases toward specific stem cell subsets that differ from previous models of GATA2 loss. Supporting this observation, single-cell RNA sequencing of hematopoietic progenitors revealed a loss of stemness, myeloid-bias, and indications of accelerated aging. Importantly, we show that Gata2R396Q/+ exerts effects early in hematopoietic development, as mutant mice generate fewer HSCs in the aorta gonad mesonephros, and fetal liver HSCs have reduced function. This reduced and altered pool of HSCs could be potential contributors to leukemic transformation in patients, and our model provides a useful tool to study the mechanisms of malignant transformation in GATA2 deficiency.
{"title":"Modeling GATA2 deficiency in mice: the R396Q mutation disrupts normal hematopoiesis","authors":"Trent Hall, Rashid Mehmood, Diana Sá da Bandeira, Anitria Cotton, Jonathon Klein, Shondra M. Pruett-Miller, Shai Izraeli, Wilson K. Clements, John D. Crispino","doi":"10.1038/s41375-024-02508-z","DOIUrl":"10.1038/s41375-024-02508-z","url":null,"abstract":"GATA2 deficiency is an autosomal dominant germline disorder of immune dysfunction and bone marrow failure with a high propensity for leukemic transformation. While sequencing studies have identified several secondary mutations thought to contribute to malignancy, the mechanisms of disease progression have been difficult to identify due to a lack of disease-specific experimental models. Here, we describe a murine model of one of the most common GATA2 mutations associated with leukemic progression in GATA2 deficiency, Gata2R396Q/+. While mutant mice exhibit mild defects in peripheral blood, they display significant hematopoietic abnormalities in the bone marrow, including a reduction in hematopoietic stem cell (HSC) function and intrinsic biases toward specific stem cell subsets that differ from previous models of GATA2 loss. Supporting this observation, single-cell RNA sequencing of hematopoietic progenitors revealed a loss of stemness, myeloid-bias, and indications of accelerated aging. Importantly, we show that Gata2R396Q/+ exerts effects early in hematopoietic development, as mutant mice generate fewer HSCs in the aorta gonad mesonephros, and fetal liver HSCs have reduced function. This reduced and altered pool of HSCs could be potential contributors to leukemic transformation in patients, and our model provides a useful tool to study the mechanisms of malignant transformation in GATA2 deficiency.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 3","pages":"734-747"},"PeriodicalIF":12.8,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02508-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142934497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-07DOI: 10.1038/s41375-024-02509-y
Reinhard Brunmeir, Li Ying, Junli Yan, Yan Ting Hee, Baohong Lin, Harvinder Kaur, Qiao Zheng Leong, Wei Wen Teo, Gerald Choong, Wei-Ying Jen, Liang Piu Koh, Lip Kun Tan, Esther Chan, Melissa Ooi, Henry Yang, Wee Joo Chng
The polycomb protein EZH2 is up-regulated in Chronic Myeloid Leukaemia (CML) and associated with transcriptional reprogramming. Here we tested whether EZH2 might also act as a modulator of the mRNA splicing landscape to elicit its oncogenic function in CML. We treated CML cell lines with EZH2 inhibitors and detected differential splicing of several hundreds of events, potentially caused by the transcriptional regulation of splicing factors. Amongst those genes, CELF2 was identified as a candidate to mediate part of the EZH2 inhibitor induced phenotype. Upon over-expression, we observed (1) reduced cell growth, viability, and colony formation of CML cell lines, (2) a change in the splicing landscape, partially overlapping with EZH2 mediated changes, (3) the down-regulation of MYC signalling. Importantly, these findings were successfully validated in a cohort of CML patient samples, confirming the role of CELF2 as EZH2-regulated tumour-suppressor, contributing to the severe splicing de-regulation present in CML. Based on this we propose that EZH2 exerts part of its oncogenic function in CML through the transcriptional repression of splicing factors. Finally, analysis of publicly available datasets suggests that splicing modulation by EZH2 might not be restricted to CML.
{"title":"EZH2 modulates mRNA splicing and exerts part of its oncogenic function through repression of splicing factors in CML","authors":"Reinhard Brunmeir, Li Ying, Junli Yan, Yan Ting Hee, Baohong Lin, Harvinder Kaur, Qiao Zheng Leong, Wei Wen Teo, Gerald Choong, Wei-Ying Jen, Liang Piu Koh, Lip Kun Tan, Esther Chan, Melissa Ooi, Henry Yang, Wee Joo Chng","doi":"10.1038/s41375-024-02509-y","DOIUrl":"10.1038/s41375-024-02509-y","url":null,"abstract":"The polycomb protein EZH2 is up-regulated in Chronic Myeloid Leukaemia (CML) and associated with transcriptional reprogramming. Here we tested whether EZH2 might also act as a modulator of the mRNA splicing landscape to elicit its oncogenic function in CML. We treated CML cell lines with EZH2 inhibitors and detected differential splicing of several hundreds of events, potentially caused by the transcriptional regulation of splicing factors. Amongst those genes, CELF2 was identified as a candidate to mediate part of the EZH2 inhibitor induced phenotype. Upon over-expression, we observed (1) reduced cell growth, viability, and colony formation of CML cell lines, (2) a change in the splicing landscape, partially overlapping with EZH2 mediated changes, (3) the down-regulation of MYC signalling. Importantly, these findings were successfully validated in a cohort of CML patient samples, confirming the role of CELF2 as EZH2-regulated tumour-suppressor, contributing to the severe splicing de-regulation present in CML. Based on this we propose that EZH2 exerts part of its oncogenic function in CML through the transcriptional repression of splicing factors. Finally, analysis of publicly available datasets suggests that splicing modulation by EZH2 might not be restricted to CML.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 3","pages":"650-662"},"PeriodicalIF":12.8,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02509-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142934507","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}
Pub Date : 2025-01-05DOI: 10.1038/s41375-024-02429-x
Luca Guarnera, Carmelo Gurnari, Carlos Bravo-Perez, Arda Durmaz, Nakisha D. Williams, Hussein Awada, Naomi Kawashima, Arooj Ahmed, Serhan Unlu, Olisaemeka D. Ogbue, Christopher Haddad, Aashray Mandala, Yasuo Kubota, Juraj Bodo, Genevieve M. Crane, Heesun J. Rogers, Jaroslaw P. Maciejewski, Valeria Visconte
{"title":"Non canonical c-CBL mutations define a specific phenotype of myeloid neoplasia","authors":"Luca Guarnera, Carmelo Gurnari, Carlos Bravo-Perez, Arda Durmaz, Nakisha D. Williams, Hussein Awada, Naomi Kawashima, Arooj Ahmed, Serhan Unlu, Olisaemeka D. Ogbue, Christopher Haddad, Aashray Mandala, Yasuo Kubota, Juraj Bodo, Genevieve M. Crane, Heesun J. Rogers, Jaroslaw P. Maciejewski, Valeria Visconte","doi":"10.1038/s41375-024-02429-x","DOIUrl":"10.1038/s41375-024-02429-x","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 3","pages":"748-751"},"PeriodicalIF":12.8,"publicationDate":"2025-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02429-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142925085","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}
Pub Date : 2024-12-23DOI: 10.1038/s41375-024-02496-0
Shivani Handa, Christoph Schaniel, Joseph Tripodi, Daiva Ahire, Md. Babu Mia, Sophie Klingborg, Douglas Tremblay, Bridget K. Marcellino, Ronald Hoffman, Vesna Najfeld
Although multiple genetic events are thought to play a role in promoting progression of the myeloproliferative neoplasms (MPN), the individual events that are associated with the development of more aggressive disease phenotypes remain poorly defined. Here, we report that novel genomic deletions at chromosome 12q14.3, as detected by a high-resolution array comparative genomic hybridization plus single nucleotide polymorphisms platform, occur in 11% of MPN patients with myelofibrosis (MF) and MPN-accelerated/blast phase (AP/BP) but was not detected in patients with polycythemia vera or essential thrombocythemia. These 12q14.3 deletions resulted in the loss of most of the non-coding region of exon 5 and MIRLET7 binding sites in the 3’UTR of the high mobility group AT hook 2 (HMGA2), which negatively regulate HMGA2 expression. These acquired 12q14.3 deletions were predominately detected in MF patients with CALR and ASXL1 co-mutations and led to a greater degree of HMGA2 transcript overexpression, independent of the presence of an ASXL1 mutation. Patients with 12q structural abnormalities involving HMGA2 exhibited a more aggressive clinical course, with a higher frequency of MPN-AP/BP evolution. These findings indicate that HMGA2 overexpression associated with genomic deletion of its 3’UTR region is a newly recognized genetic event that contributes to MPN progression.
{"title":"HMGA2 overexpression with specific chromosomal abnormalities predominate in CALR and ASXL1 mutated myelofibrosis","authors":"Shivani Handa, Christoph Schaniel, Joseph Tripodi, Daiva Ahire, Md. Babu Mia, Sophie Klingborg, Douglas Tremblay, Bridget K. Marcellino, Ronald Hoffman, Vesna Najfeld","doi":"10.1038/s41375-024-02496-0","DOIUrl":"10.1038/s41375-024-02496-0","url":null,"abstract":"Although multiple genetic events are thought to play a role in promoting progression of the myeloproliferative neoplasms (MPN), the individual events that are associated with the development of more aggressive disease phenotypes remain poorly defined. Here, we report that novel genomic deletions at chromosome 12q14.3, as detected by a high-resolution array comparative genomic hybridization plus single nucleotide polymorphisms platform, occur in 11% of MPN patients with myelofibrosis (MF) and MPN-accelerated/blast phase (AP/BP) but was not detected in patients with polycythemia vera or essential thrombocythemia. These 12q14.3 deletions resulted in the loss of most of the non-coding region of exon 5 and MIRLET7 binding sites in the 3’UTR of the high mobility group AT hook 2 (HMGA2), which negatively regulate HMGA2 expression. These acquired 12q14.3 deletions were predominately detected in MF patients with CALR and ASXL1 co-mutations and led to a greater degree of HMGA2 transcript overexpression, independent of the presence of an ASXL1 mutation. Patients with 12q structural abnormalities involving HMGA2 exhibited a more aggressive clinical course, with a higher frequency of MPN-AP/BP evolution. These findings indicate that HMGA2 overexpression associated with genomic deletion of its 3’UTR region is a newly recognized genetic event that contributes to MPN progression.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 3","pages":"663-674"},"PeriodicalIF":12.8,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02496-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142873946","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}
Pub Date : 2024-12-20DOI: 10.1038/s41375-024-02503-4
Qian Cui, Wen Tan, Bao Song, Rou-Jun Peng, Ling Wang, Rajkumar Dorajoo, Kok Pin Ng, Guo-Wang Lin, Wing-Yan Au, Raymond H. S. Liang, Chiea Chuen Khor, Qing-Ling Zhang, Jia Nee FOO, Sheng-Ping Li, Fu-Ren Zhang, Xue-Jun Zhang, Xue-Qing Yu, Qing Lan, Stephen Chanock, Wei-Hua Jia, Soon Thye Lim, Wen-Yu Li, Nathaniel Rothman, Jin-Xin Bei, Jie Liu, Dongxin Lin, Jian-Jun Liu
Diffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy and the most common form of non-Hodgkin lymphoma (NHL) that occurs worldwide. To discover risk factors and pathogenesis of DLBCL, we performed the largest GWAS of DLBCL to date in samples of East Asian ancestry, consisting of 2,888 patients with DLBCL and 12,458 controls. The meta-analysis identified three novel loci, rs2233434 on 6p21.1 (OR = 1.26, P = 1.17 × 10−8), rs11066015 on 12q24.12 (OR = 1.24, P = 6.57 × 10−9) and rs6032662 on 20q13.12 (OR = 1.24, P = 5.22 × 10−12). Fine mapping analysis revealed that the extensive association within the MHC region was driven by two novel HLA alleles, HLA-A*02 and HLA-DQB1*03. Functional annotation, eQTL and colocalization analyses of the susceptibility loci implicated NFKBIE/TCTE1, ALDH2/BRAP and CD40 as candidate disease genes. The pleiotropic effect analysis of the DLBCL loci revealed shared genetic susceptibility between DLBCL and several autoimmune diseases. Our study also suggested genetic heterogeneity between Asian and European populations by identifying ancestry-specific genetic associations. Overall, this study has implicated novel disease genes and molecular mechanism for DLBCL.
{"title":"Genetic susceptibility of diffuse large B-cell lymphoma: a meta genome-wide association study in Asian population","authors":"Qian Cui, Wen Tan, Bao Song, Rou-Jun Peng, Ling Wang, Rajkumar Dorajoo, Kok Pin Ng, Guo-Wang Lin, Wing-Yan Au, Raymond H. S. Liang, Chiea Chuen Khor, Qing-Ling Zhang, Jia Nee FOO, Sheng-Ping Li, Fu-Ren Zhang, Xue-Jun Zhang, Xue-Qing Yu, Qing Lan, Stephen Chanock, Wei-Hua Jia, Soon Thye Lim, Wen-Yu Li, Nathaniel Rothman, Jin-Xin Bei, Jie Liu, Dongxin Lin, Jian-Jun Liu","doi":"10.1038/s41375-024-02503-4","DOIUrl":"10.1038/s41375-024-02503-4","url":null,"abstract":"Diffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy and the most common form of non-Hodgkin lymphoma (NHL) that occurs worldwide. To discover risk factors and pathogenesis of DLBCL, we performed the largest GWAS of DLBCL to date in samples of East Asian ancestry, consisting of 2,888 patients with DLBCL and 12,458 controls. The meta-analysis identified three novel loci, rs2233434 on 6p21.1 (OR = 1.26, P = 1.17 × 10−8), rs11066015 on 12q24.12 (OR = 1.24, P = 6.57 × 10−9) and rs6032662 on 20q13.12 (OR = 1.24, P = 5.22 × 10−12). Fine mapping analysis revealed that the extensive association within the MHC region was driven by two novel HLA alleles, HLA-A*02 and HLA-DQB1*03. Functional annotation, eQTL and colocalization analyses of the susceptibility loci implicated NFKBIE/TCTE1, ALDH2/BRAP and CD40 as candidate disease genes. The pleiotropic effect analysis of the DLBCL loci revealed shared genetic susceptibility between DLBCL and several autoimmune diseases. Our study also suggested genetic heterogeneity between Asian and European populations by identifying ancestry-specific genetic associations. Overall, this study has implicated novel disease genes and molecular mechanism for DLBCL.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 3","pages":"694-702"},"PeriodicalIF":12.8,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02503-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858429","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}
Pub Date : 2024-12-19DOI: 10.1038/s41375-024-02502-5
Aurélie Caye-Eude, Grazia Fazio, Agata Pastorczak, Judith M. Boer, Doris Steinemann, Debdutta Ganguli, Edwin Sonneveld, Sabrina Haslinger, Lucía D’Andrea, Jutta Bradtke, Bruno A. Lopes, Marketa Zaliova, Gabriele Escherich, Margit König, Klaus Fortschegger, Andrea Inthal, Irina Stasevich, Mariana Emerenciano, Jan Trka, Luis Castillo, Mayur Parihar, Anthony V. Moorman, Anke K. Bergmann, Monique L. den Boer, Wojciech Młynarski, Giovanni Cazzaniga, Hélène Cavé, Karin Nebral, Dagmar Schinnerl, Sabine Strehl
{"title":"PAX5::AUTS2 childhood B-ALL: a relapse-prone genetic subtype with frequent central nervous system involvement and a poor outcome","authors":"Aurélie Caye-Eude, Grazia Fazio, Agata Pastorczak, Judith M. Boer, Doris Steinemann, Debdutta Ganguli, Edwin Sonneveld, Sabrina Haslinger, Lucía D’Andrea, Jutta Bradtke, Bruno A. Lopes, Marketa Zaliova, Gabriele Escherich, Margit König, Klaus Fortschegger, Andrea Inthal, Irina Stasevich, Mariana Emerenciano, Jan Trka, Luis Castillo, Mayur Parihar, Anthony V. Moorman, Anke K. Bergmann, Monique L. den Boer, Wojciech Młynarski, Giovanni Cazzaniga, Hélène Cavé, Karin Nebral, Dagmar Schinnerl, Sabine Strehl","doi":"10.1038/s41375-024-02502-5","DOIUrl":"10.1038/s41375-024-02502-5","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 2","pages":"482-486"},"PeriodicalIF":12.8,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02502-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848835","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}
Recent extensive studies on the genomic and molecular profiles of acute myeloid leukemia (AML) have expanded the treatment options, including, a range of compounds represented by fms-like tyrosine kinase 3 and isocitrate dehydrogenase 1/2 inhibitors. However, despite this progress, further treatments for AML are still required. Adenosine deaminase acting on RNA 1 (ADAR1) has been shown to play an important oncogenic role in many cancers, but its involvement in AML progression remains underexplored. In this study, we demonstrated that ADAR1 was overexpressed in AML and served as a crucial oncogenic target. Loss of ADAR1 inhibited the Wnt signaling pathway, blocked AML cell proliferation, and induced apoptosis. Importantly, we demonstrate that ADAR1, as an RNA-binding protein, interacts with pri-miR-766 independently of its editing function, regulating the maturation of miR-766-3p and enhancing the expression of WNT5B. Genetic inhibition or use of the ADAR1 inhibitor ZYS-1 significantly suppressed AML cell growth both in vitro and in vivo. Overall, these results elucidated the tumorigenic mechanism of ADAR1 and validated it as a potential drug target in AML.
{"title":"ADAR1 is required for acute myeloid leukemia cell survival by modulating post-transcriptional Wnt signaling through impairing miRNA biogenesis","authors":"Zhongrui Shi, Jiaxing Li, Jiayu Ding, Yiwen Zhang, Wenjian Min, Yasheng Zhu, Yi Hou, Kai Yuan, Chengliang Sun, Xuejiao Wang, Hao Shen, Liping Wang, Shun-Qing Liang, Wenbin Kuang, Xiao Wang, Peng Yang","doi":"10.1038/s41375-024-02500-7","DOIUrl":"10.1038/s41375-024-02500-7","url":null,"abstract":"Recent extensive studies on the genomic and molecular profiles of acute myeloid leukemia (AML) have expanded the treatment options, including, a range of compounds represented by fms-like tyrosine kinase 3 and isocitrate dehydrogenase 1/2 inhibitors. However, despite this progress, further treatments for AML are still required. Adenosine deaminase acting on RNA 1 (ADAR1) has been shown to play an important oncogenic role in many cancers, but its involvement in AML progression remains underexplored. In this study, we demonstrated that ADAR1 was overexpressed in AML and served as a crucial oncogenic target. Loss of ADAR1 inhibited the Wnt signaling pathway, blocked AML cell proliferation, and induced apoptosis. Importantly, we demonstrate that ADAR1, as an RNA-binding protein, interacts with pri-miR-766 independently of its editing function, regulating the maturation of miR-766-3p and enhancing the expression of WNT5B. Genetic inhibition or use of the ADAR1 inhibitor ZYS-1 significantly suppressed AML cell growth both in vitro and in vivo. Overall, these results elucidated the tumorigenic mechanism of ADAR1 and validated it as a potential drug target in AML.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 3","pages":"599-613"},"PeriodicalIF":12.8,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02500-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848836","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}
Pub Date : 2024-12-17DOI: 10.1038/s41375-024-02476-4
Brunangelo Falini, Daniele Sorcini, Vincenzo Maria Perriello, Paolo Sportoletti
The nucleophosmin (NPM1) gene encodes for the most abundant nucleolar protein. Thanks to its property to act as histone chaperone and to shuttle between the nucleus and cytoplasm, the NPM1 protein is involved in multiple cellular function that are here extensively reviewed and include the formation of the nucleolus through liquid-liquid phase separation, regulation of ribosome biogenesis and transport, control of DNA repair and centrosome duplication as well as response to nucleolar stress. NPM1 is mutated in about 30–35% of adult acute myeloid leukemia (AML). Due to its unique biological and clinical features, NPM1-mutated AML is regarded as a distinct leukemia entity in the WHO 5th edition and ICC classifications of myeloid malignancies. The NPM1 mutant undergoes changes at the C-terminus of the protein that leads to its delocalization in the cytoplasm of the leukemic cells. Here, we focus also on its biological functions discussing the murine models of NPM1 mutations and the various mechanisms that occur at cytoplasmic and nuclear levels to promote and maintain NPM1-mutated AML
{"title":"Functions of the native NPM1 protein and its leukemic mutant","authors":"Brunangelo Falini, Daniele Sorcini, Vincenzo Maria Perriello, Paolo Sportoletti","doi":"10.1038/s41375-024-02476-4","DOIUrl":"10.1038/s41375-024-02476-4","url":null,"abstract":"The nucleophosmin (NPM1) gene encodes for the most abundant nucleolar protein. Thanks to its property to act as histone chaperone and to shuttle between the nucleus and cytoplasm, the NPM1 protein is involved in multiple cellular function that are here extensively reviewed and include the formation of the nucleolus through liquid-liquid phase separation, regulation of ribosome biogenesis and transport, control of DNA repair and centrosome duplication as well as response to nucleolar stress. NPM1 is mutated in about 30–35% of adult acute myeloid leukemia (AML). Due to its unique biological and clinical features, NPM1-mutated AML is regarded as a distinct leukemia entity in the WHO 5th edition and ICC classifications of myeloid malignancies. The NPM1 mutant undergoes changes at the C-terminus of the protein that leads to its delocalization in the cytoplasm of the leukemic cells. Here, we focus also on its biological functions discussing the murine models of NPM1 mutations and the various mechanisms that occur at cytoplasmic and nuclear levels to promote and maintain NPM1-mutated AML","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 2","pages":"276-290"},"PeriodicalIF":12.8,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02476-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142832005","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}
Pub Date : 2024-12-17DOI: 10.1038/s41375-024-02499-x
Jana Nabki, Bashar Al Deeban, Abel Mehari Sium, Chiara Cosentino, Mohammad Almasri, Bassel Awikeh, Nawar Maher, Matteo Bellia, Riccardo Dondolin, Samir Mouhssine, Donatella Talotta, Eleonora Secomandi, Sreekar Kogila, Joseph Ghanej, Francesca Maiellaro, Luca Cividini, Silvia Rasi, Annalisa Chiarenza, Jacopo Olivieri, Massimo Gentile, Francesco Zaja, Maria Ilaria Del Principe, Luca Laurenti, Riccardo Bomben, Filippo Vit, Tamara Bittolo, Antonella Zucchetto, Valter Gattei, Gianluca Gaidano, Riccardo Moia
The mutational status of immunoglobulin (IG) light chain genes in chronic lymphocytic leukemia (CLL) and its clinical impact have not been extensively studied. To assess their prognostic significance, the IG light chain gene repertoire in CLL patients has been evaluated using a training-validation approach. In the training cohort (N = 573 CLL), 92.5% showed productive IG light chain genes rearrangements, with IGKV4-1 (20.5%) and IGLV3-21 (19.0%) being the most common. A 99.0% somatic hypermutation cut-off was identified as the best predictor for time to first treatment (TTFT) in 414 Binet A CLL patients of the training cohort. Patients with unmutated (UM) light chain genes displayed a 10-year treatment free probability of 32.4% versus 73.2% for those with mutated (M) genes (p < 0.0001). Importantly, UM light chain genes maintained an independent association with a shorter TTFT when adjusted for the IPS-E prognostic model variables, that also includes IGHV mutational status. The validation cohort of 343 Rai 0 patients confirmed these findings, with UM light chain genes predicting a 7-year treatment free probability of 42.0% versus 73.7% for M genes (p < 0.0001). These results indicate that the mutational status of the light chain genes is an independent predictor of shorter TTFT in early-stage CLL patients.
{"title":"Immunoglobulin light chain mutational status refines IGHV prognostic value in identifying chronic lymphocytic leukemia patients with early treatment requirement","authors":"Jana Nabki, Bashar Al Deeban, Abel Mehari Sium, Chiara Cosentino, Mohammad Almasri, Bassel Awikeh, Nawar Maher, Matteo Bellia, Riccardo Dondolin, Samir Mouhssine, Donatella Talotta, Eleonora Secomandi, Sreekar Kogila, Joseph Ghanej, Francesca Maiellaro, Luca Cividini, Silvia Rasi, Annalisa Chiarenza, Jacopo Olivieri, Massimo Gentile, Francesco Zaja, Maria Ilaria Del Principe, Luca Laurenti, Riccardo Bomben, Filippo Vit, Tamara Bittolo, Antonella Zucchetto, Valter Gattei, Gianluca Gaidano, Riccardo Moia","doi":"10.1038/s41375-024-02499-x","DOIUrl":"10.1038/s41375-024-02499-x","url":null,"abstract":"The mutational status of immunoglobulin (IG) light chain genes in chronic lymphocytic leukemia (CLL) and its clinical impact have not been extensively studied. To assess their prognostic significance, the IG light chain gene repertoire in CLL patients has been evaluated using a training-validation approach. In the training cohort (N = 573 CLL), 92.5% showed productive IG light chain genes rearrangements, with IGKV4-1 (20.5%) and IGLV3-21 (19.0%) being the most common. A 99.0% somatic hypermutation cut-off was identified as the best predictor for time to first treatment (TTFT) in 414 Binet A CLL patients of the training cohort. Patients with unmutated (UM) light chain genes displayed a 10-year treatment free probability of 32.4% versus 73.2% for those with mutated (M) genes (p < 0.0001). Importantly, UM light chain genes maintained an independent association with a shorter TTFT when adjusted for the IPS-E prognostic model variables, that also includes IGHV mutational status. The validation cohort of 343 Rai 0 patients confirmed these findings, with UM light chain genes predicting a 7-year treatment free probability of 42.0% versus 73.7% for M genes (p < 0.0001). These results indicate that the mutational status of the light chain genes is an independent predictor of shorter TTFT in early-stage CLL patients.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 3","pages":"643-649"},"PeriodicalIF":12.8,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02499-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142832004","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}
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