Pub Date : 2026-01-15DOI: 10.3324/haematol.2024.287013
Amy P Hsu, Subrata Paul, Jennifer L Kwan, Philip L F Johnson, Justin Lack, Eva P Szymanski, Jana Lovell, Ladan Foruraghi, Cindy Palmer, Christa S Zerbe, Janine R Daub, Joie Davis, Dennis D Hickstein, Katherine R Calvo, Steven M Holland
GATA2 mutations cause adult-onset bone-marrow failure characterized by cytopenias, infections and increased risk of myeloid malignancy. We reviewed hospital records and referrals of 232 GATA2 mutated individuals from 122 families to gather hematopoietic and syndromic features. Mutations were categorized by GATA2 protein effect: mutation after the 2nd Zinc-finger (Cterm, n=10); missense in the 2nd Zinc-Finger (ZF2, n=104); mutations producing stable truncated protein (Truncation, n=22); Null alleles (mRNA instability, large deletions, n=46); or Enhancer (n=50). Regression models for symptom onset identified earlier onset and increased hazard ratios (HR) between Truncation, Null or ZF2 mutations (13 years, HR 5.00; 17 years, 3.60; 22 years, 2.23 respectively) and Enhancer. Commonly mutated ZF2 amino acids stratified: R396 or T354 presented earlier with increased hazard ratios (16 years, HR 2.96; 19 years, HR 2.16) versus R398 (34 years). Mutation groups with median onset.
{"title":"GATA2 at 14: genotype-phenotype correlations.","authors":"Amy P Hsu, Subrata Paul, Jennifer L Kwan, Philip L F Johnson, Justin Lack, Eva P Szymanski, Jana Lovell, Ladan Foruraghi, Cindy Palmer, Christa S Zerbe, Janine R Daub, Joie Davis, Dennis D Hickstein, Katherine R Calvo, Steven M Holland","doi":"10.3324/haematol.2024.287013","DOIUrl":"https://doi.org/10.3324/haematol.2024.287013","url":null,"abstract":"<p><p>GATA2 mutations cause adult-onset bone-marrow failure characterized by cytopenias, infections and increased risk of myeloid malignancy. We reviewed hospital records and referrals of 232 GATA2 mutated individuals from 122 families to gather hematopoietic and syndromic features. Mutations were categorized by GATA2 protein effect: mutation after the 2nd Zinc-finger (Cterm, n=10); missense in the 2nd Zinc-Finger (ZF2, n=104); mutations producing stable truncated protein (Truncation, n=22); Null alleles (mRNA instability, large deletions, n=46); or Enhancer (n=50). Regression models for symptom onset identified earlier onset and increased hazard ratios (HR) between Truncation, Null or ZF2 mutations (13 years, HR 5.00; 17 years, 3.60; 22 years, 2.23 respectively) and Enhancer. Commonly mutated ZF2 amino acids stratified: R396 or T354 presented earlier with increased hazard ratios (16 years, HR 2.96; 19 years, HR 2.16) versus R398 (34 years). Mutation groups with median onset.</p>","PeriodicalId":12964,"journal":{"name":"Haematologica","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145970705","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 : 2026-01-15DOI: 10.3324/haematol.2025.300036
Naveen Pemmaraju,Marco Herling,Kendra L Sweet,Anthony S Stein,Sumithira Vasu,Todd L Rosenblat,David A Rizzieri,Cristina Papayannidis,Eunice S Wang,Marina Konopleva,Michael Zuurman,Alessandra Tosolini,Muzaffar Qazilbash,Andrew A Lane
Not available.
不可用。
{"title":"First-line tagraxofusp leads to durable responses and prolonged survival in adults with blastic plasmacytoid dendritic cell neoplasm regardless of fitness level.","authors":"Naveen Pemmaraju,Marco Herling,Kendra L Sweet,Anthony S Stein,Sumithira Vasu,Todd L Rosenblat,David A Rizzieri,Cristina Papayannidis,Eunice S Wang,Marina Konopleva,Michael Zuurman,Alessandra Tosolini,Muzaffar Qazilbash,Andrew A Lane","doi":"10.3324/haematol.2025.300036","DOIUrl":"https://doi.org/10.3324/haematol.2025.300036","url":null,"abstract":"Not available.","PeriodicalId":12964,"journal":{"name":"Haematologica","volume":"30 1","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145968698","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 : 2026-01-15DOI: 10.3324/haematol.2025.289218
Eli Muchtar,Giovanni Palladini,Stefan Schonland,Susan Geyer,Katharine E Dooley,Angela Dispenzieri,Brendan Wisniowski,Giampaolo Merlini,Paolo Milani,Ute Hegenbart,Tobias Dittrich,Efstathios Kastritis,Meletios A Dimopoulos,Vaishali Sanchorawala,Raphael Szalat,Michaela Liedtke,Mani Gupta,Heather Landau,Suzanne Lentzsch,Michael S Hughes,Maria Teresa Cibeira,Joan Blade,Shaji K Kumar,Ashutosh Wechalekar,Morie A Gertz
Liver involvement in light chain amyloidosis (AL) is seen in 10-20% of patients and is associated with poor prognosis. The goal of this study was to assess the prognostic impact of the hepatic response criteria. AL patients diagnosed between 2010 and 2015 with liver involvement [serum alkaline phosphatase (AP) >1.5 upper reference limit (URL)] who achieved hematological response were included. Hepatic response was defined as >50% reduction (or normalization) of AP from baseline. Hepatic response was assessed at 6, 12, and 24-months after therapy initiation and at best response. Overall survival (OS) was assessed from time of therapy initiation. Hepatic response was evaluated in 116 patients. The median baseline serum AP was X2.6 URL. Hematological very good partial response (VGPR) or better was achieved in 69% of patients. AP decreased with time, with a median reduction of 22%, 34%, and 53% at 6-, 12-, and 24-months, respectively, and a median AP reduction of 56% at the time of best response. The median time to hepatic response was 13.3 months and was longer for patients undergoing autologous stem cell transplantation. Achievement of hepatic response, particularly as early as 12 months, and at best response, was associated with improved survival, independent of other prognostic factors. Predictors of hepatic response include higher baseline AP level, lower total bilirubin, hematological ≥VGPR, and cardiac and renal responses, when applicable. Hepatic response measured by the change in alkaline phosphatase is a prognostic factor in patients with AL amyloidosis.
{"title":"Hepatic response criteria in light chain amyloidosis: a multicenter validation study.","authors":"Eli Muchtar,Giovanni Palladini,Stefan Schonland,Susan Geyer,Katharine E Dooley,Angela Dispenzieri,Brendan Wisniowski,Giampaolo Merlini,Paolo Milani,Ute Hegenbart,Tobias Dittrich,Efstathios Kastritis,Meletios A Dimopoulos,Vaishali Sanchorawala,Raphael Szalat,Michaela Liedtke,Mani Gupta,Heather Landau,Suzanne Lentzsch,Michael S Hughes,Maria Teresa Cibeira,Joan Blade,Shaji K Kumar,Ashutosh Wechalekar,Morie A Gertz","doi":"10.3324/haematol.2025.289218","DOIUrl":"https://doi.org/10.3324/haematol.2025.289218","url":null,"abstract":"Liver involvement in light chain amyloidosis (AL) is seen in 10-20% of patients and is associated with poor prognosis. The goal of this study was to assess the prognostic impact of the hepatic response criteria. AL patients diagnosed between 2010 and 2015 with liver involvement [serum alkaline phosphatase (AP) >1.5 upper reference limit (URL)] who achieved hematological response were included. Hepatic response was defined as >50% reduction (or normalization) of AP from baseline. Hepatic response was assessed at 6, 12, and 24-months after therapy initiation and at best response. Overall survival (OS) was assessed from time of therapy initiation. Hepatic response was evaluated in 116 patients. The median baseline serum AP was X2.6 URL. Hematological very good partial response (VGPR) or better was achieved in 69% of patients. AP decreased with time, with a median reduction of 22%, 34%, and 53% at 6-, 12-, and 24-months, respectively, and a median AP reduction of 56% at the time of best response. The median time to hepatic response was 13.3 months and was longer for patients undergoing autologous stem cell transplantation. Achievement of hepatic response, particularly as early as 12 months, and at best response, was associated with improved survival, independent of other prognostic factors. Predictors of hepatic response include higher baseline AP level, lower total bilirubin, hematological ≥VGPR, and cardiac and renal responses, when applicable. Hepatic response measured by the change in alkaline phosphatase is a prognostic factor in patients with AL amyloidosis.","PeriodicalId":12964,"journal":{"name":"Haematologica","volume":"49 1","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145968701","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 : 2026-01-15DOI: 10.3324/haematol.2025.288785
Sabine Kayser,Richard F Schlenk
{"title":"All patients with AML and FLT3-ITD should be transplanted in first remission. Also in the era of tyrosine kinase inhibitors? - the PRO","authors":"Sabine Kayser,Richard F Schlenk","doi":"10.3324/haematol.2025.288785","DOIUrl":"https://doi.org/10.3324/haematol.2025.288785","url":null,"abstract":"","PeriodicalId":12964,"journal":{"name":"Haematologica","volume":"1 1","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145968702","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 : 2026-01-15DOI: 10.3324/haematol.2025.288461
Cecilia C S Yeung,Stephen M Eacker,Olga Sala-Torra,Mary Wood,Lan Beppu,David W Woolston,Ivan Liachko,Maika Malig,Derek Stirewalt,Alexander Muratov,Min Fang,Jerald Radich
Cytogenetic analysis encompasses a suite of standard-of-care diagnostic testing methods that is applied routinely in cases of acute myeloid leukemia (AML) to assess chromosomal changes that are clinically relevant for risk classification and treatment decisions. In this study, we assess the use of Genomic Proximity Mapping® (GPM) for cytogenomic analysis of AML diagnostic specimens for detection of cytogenetic risk variants included in the European Leukemia Network (ELN) risk stratification guidelines. Archival patient samples (n = 48) from the Fred Hutchinson Cancer Center (FH) leukemia bank with historical clinical cytogenetic data were processed for GPM and analyzed with the CytoTerra cloud-based analysis platform. Genomic proximity mapping showed 100% concordance for all specific variants that have associated impacts on risk stratification as defined by ELN 2022 criteria and 78% concordance when considering all variants reported by the FH Cytogenetics Lab. Notably, the percentage of blasts (ranging from 5- 96%) did not have a clear effect on the ability to detect these variants. In two cases, GPM identified a recurrent inv(9)(p13.3p13.1). These findings demonstrate GPM's effectiveness for the evaluation of known AML-associated risk variants and a source for biomarker discovery.
细胞遗传学分析包括一套标准诊断测试方法，用于急性髓性白血病（AML）病例的常规评估染色体变化，这些变化与临床风险分类和治疗决策相关。在这项研究中，我们评估了使用基因组接近定位®（GPM）对AML诊断标本进行细胞基因组分析，以检测欧洲白血病网络（ELN）风险分层指南中包含的细胞遗传学风险变异。来自Fred Hutchinson Cancer Center （FH）白血病库的档案患者样本（n = 48）具有历史临床细胞遗传学数据，并使用基于CytoTerra的云分析平台进行GPM处理和分析。基因组接近图谱显示，与ELN 2022标准定义的风险分层相关的所有特定变异的一致性为100%，考虑到FH细胞遗传学实验室报告的所有变异，一致性为78%。值得注意的是，爆炸的百分比（范围从5%到96%）对检测这些变异的能力没有明显的影响。在两个病例中，GPM发现了复发性inv(9)（p13.3p13.1）。这些发现证明了GPM在评估已知aml相关风险变异方面的有效性，也是发现生物标志物的来源。
{"title":"Evaluation of acute myeloid leukemia using genomic proximity mapping-based next generation cytogenomics.","authors":"Cecilia C S Yeung,Stephen M Eacker,Olga Sala-Torra,Mary Wood,Lan Beppu,David W Woolston,Ivan Liachko,Maika Malig,Derek Stirewalt,Alexander Muratov,Min Fang,Jerald Radich","doi":"10.3324/haematol.2025.288461","DOIUrl":"https://doi.org/10.3324/haematol.2025.288461","url":null,"abstract":"Cytogenetic analysis encompasses a suite of standard-of-care diagnostic testing methods that is applied routinely in cases of acute myeloid leukemia (AML) to assess chromosomal changes that are clinically relevant for risk classification and treatment decisions. In this study, we assess the use of Genomic Proximity Mapping® (GPM) for cytogenomic analysis of AML diagnostic specimens for detection of cytogenetic risk variants included in the European Leukemia Network (ELN) risk stratification guidelines. Archival patient samples (n = 48) from the Fred Hutchinson Cancer Center (FH) leukemia bank with historical clinical cytogenetic data were processed for GPM and analyzed with the CytoTerra cloud-based analysis platform. Genomic proximity mapping showed 100% concordance for all specific variants that have associated impacts on risk stratification as defined by ELN 2022 criteria and 78% concordance when considering all variants reported by the FH Cytogenetics Lab. Notably, the percentage of blasts (ranging from 5- 96%) did not have a clear effect on the ability to detect these variants. In two cases, GPM identified a recurrent inv(9)(p13.3p13.1). These findings demonstrate GPM's effectiveness for the evaluation of known AML-associated risk variants and a source for biomarker discovery.","PeriodicalId":12964,"journal":{"name":"Haematologica","volume":"2 1","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145968710","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 : 2026-01-08DOI: 10.3324/haematol.2025.288522
Rialnat A Lawal, Fernanda Gutierrez-Rodrigues, David J Young, Erica Bresciani, Emma M Groarke, Natalie T Deuitch, Molly McGuinness, Kathleen Craft, Shawn Chong, Michael Sierk, Daoud Meerzaman, Bhavisha A Patel, Neal S Young, Nan-Ping Weng, Paul P Liu
Not available.
不可用。
{"title":"Telomere attrition is common in patients with germline <i>RUNX1</i> pathogenic variants.","authors":"Rialnat A Lawal, Fernanda Gutierrez-Rodrigues, David J Young, Erica Bresciani, Emma M Groarke, Natalie T Deuitch, Molly McGuinness, Kathleen Craft, Shawn Chong, Michael Sierk, Daoud Meerzaman, Bhavisha A Patel, Neal S Young, Nan-Ping Weng, Paul P Liu","doi":"10.3324/haematol.2025.288522","DOIUrl":"https://doi.org/10.3324/haematol.2025.288522","url":null,"abstract":"<p><p>Not available.</p>","PeriodicalId":12964,"journal":{"name":"Haematologica","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145932975","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 : 2026-01-08DOI: 10.3324/haematol.2025.287966
Linde Van Aerschot, Sofie Demeyer, Kalina Timcheva, Elien Heylen, Paulien Verstraete, Dylan De Groote, Marino Caruso, Lukas Lauwereins, Alexandra Veloso, Kim R Kampen, Daniele Pepe, Nancy Boeckx, Jonathan Royaert, Jelle Verbeeck, Heidi Segers, Jan Cools, Kim De Keersmaecker, David Cabrerizo Granados
T-cell acute lymphoblastic leukemia (T-ALL) is characterized by ectopic expression of transcription factors, including NKX2-1, which is overexpressed in 5% of patients. NKX2-1 is associated with a cortical immunophenotype and drives metabolic addiction to the serine/glycine synthesis pathway in T-ALL. However, a complete picture of the role of NKX2-1 in T-ALL pathogenesis is missing. We characterized a CRISPR-Cas9 NKX2-1 knockout model of RPMI-8402, the only known NKX2-1-expressing T-ALL cell line, and validated obtained results in patient samples. NKX2-1 knockout caused a less mature immunophenotype and promoted cell cycle progression, in line with direct transcriptional repression of CDK6 by NKX2-1 that we observed. Furthermore, NKX2-1 protected T-ALL cells from apoptosis and DNA damage. The NKX2-1 protein directly bound DNA repair factors, such as RPA1 and RPA2, and presence of NKX2-1 resulted in differential expression of gene sets related to DNA damage repair in RPMI-8402 cells and patient samples. Furthermore, NKX2-1 positive cells showed less induction of DNA damage and apoptosis upon treatment with etoposide, a DNA damaging chemotherapy agent that is clinically used to treat T-ALL. Mechanistically, our data supported that RUNX1 is an important co-factor for NKX2-1 transcriptional regulation in T-ALL cells, and that NKX2-1 modulated the composition of RUNX1 protein complexes. Notably, NKX2-1 expressing cells showed higher sensitivity towards RUNX1 inhibition, suggesting a cooperative role in regulating T-ALL cell survival. This work reveals a critical role of NKX2-1 in enhancing T-ALL cell survival through DNA damage protection, and identifies RUNX1 as an important cofactor in T-ALL pathogenesis.
{"title":"NKX2-1 regulates cell survival, maturation, and DNA-damage responses as a cofactor of RUNX1 in T-cell acute lymphoblastic leukemia.","authors":"Linde Van Aerschot, Sofie Demeyer, Kalina Timcheva, Elien Heylen, Paulien Verstraete, Dylan De Groote, Marino Caruso, Lukas Lauwereins, Alexandra Veloso, Kim R Kampen, Daniele Pepe, Nancy Boeckx, Jonathan Royaert, Jelle Verbeeck, Heidi Segers, Jan Cools, Kim De Keersmaecker, David Cabrerizo Granados","doi":"10.3324/haematol.2025.287966","DOIUrl":"https://doi.org/10.3324/haematol.2025.287966","url":null,"abstract":"<p><p>T-cell acute lymphoblastic leukemia (T-ALL) is characterized by ectopic expression of transcription factors, including NKX2-1, which is overexpressed in 5% of patients. NKX2-1 is associated with a cortical immunophenotype and drives metabolic addiction to the serine/glycine synthesis pathway in T-ALL. However, a complete picture of the role of NKX2-1 in T-ALL pathogenesis is missing. We characterized a CRISPR-Cas9 NKX2-1 knockout model of RPMI-8402, the only known NKX2-1-expressing T-ALL cell line, and validated obtained results in patient samples. NKX2-1 knockout caused a less mature immunophenotype and promoted cell cycle progression, in line with direct transcriptional repression of CDK6 by NKX2-1 that we observed. Furthermore, NKX2-1 protected T-ALL cells from apoptosis and DNA damage. The NKX2-1 protein directly bound DNA repair factors, such as RPA1 and RPA2, and presence of NKX2-1 resulted in differential expression of gene sets related to DNA damage repair in RPMI-8402 cells and patient samples. Furthermore, NKX2-1 positive cells showed less induction of DNA damage and apoptosis upon treatment with etoposide, a DNA damaging chemotherapy agent that is clinically used to treat T-ALL. Mechanistically, our data supported that RUNX1 is an important co-factor for NKX2-1 transcriptional regulation in T-ALL cells, and that NKX2-1 modulated the composition of RUNX1 protein complexes. Notably, NKX2-1 expressing cells showed higher sensitivity towards RUNX1 inhibition, suggesting a cooperative role in regulating T-ALL cell survival. This work reveals a critical role of NKX2-1 in enhancing T-ALL cell survival through DNA damage protection, and identifies RUNX1 as an important cofactor in T-ALL pathogenesis.</p>","PeriodicalId":12964,"journal":{"name":"Haematologica","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145932868","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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