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GATA2 links stemness to chemotherapy resistance in acute myeloid leukemia.

IF 21 1区医学

Blood Pub Date : 2025-01-22 DOI: 10.1182/blood.2024025761

Fatemeh Alikarami, Hongbo M Xie, Simone S Riedel, Haley Goodrow, Declan Raymond Barrett, Leila Mahdavi, Alexandra Lenard, Changya Chen, Taylor Yamauchi, Etienne Danis, Zhendong Cao, Vu Le-Huy Tran, Mabel Minji Jung, Yapeng Li, Hua Huang, Junwei Shi, Kai Tan, David Trent Teachey, Emery H Bresnick, Tobias Neff, Kathrin Maria Bernt

{"title":"GATA2 links stemness to chemotherapy resistance in acute myeloid leukemia.","authors":"Fatemeh Alikarami, Hongbo M Xie, Simone S Riedel, Haley Goodrow, Declan Raymond Barrett, Leila Mahdavi, Alexandra Lenard, Changya Chen, Taylor Yamauchi, Etienne Danis, Zhendong Cao, Vu Le-Huy Tran, Mabel Minji Jung, Yapeng Li, Hua Huang, Junwei Shi, Kai Tan, David Trent Teachey, Emery H Bresnick, Tobias Neff, Kathrin Maria Bernt","doi":"10.1182/blood.2024025761","DOIUrl":"https://doi.org/10.1182/blood.2024025761","url":null,"abstract":"Stemness-associated cell states are linked to chemotherapy resistance in AML. We uncovered a direct mechanistic link between expression of the stem cell transcription factor GATA2 and drug resistance. The GATA-binding protein 2 (GATA2) plays a central role in blood stem cell generation and maintenance. We find substantial intra- and inter-patient variability in GATA2 expression across AML patient samples. GATA2 expression varies by molecular subtype and has been linked to outcome. In a murine model, KMT2A-MLL3 driven AML originating from a stem cell or immature progenitor cell population have higher Gata2 expression and are more resistant to the standard AML chemotherapy agent doxorubicin. Deletion of Gata2 resulted in more robust induction of p53 following exposure to doxorubicin. ChIP-Seq, RNA-Seq and functional studies revealed that GATA2 regulates the expression of RASSF4, a modulator of the p53 inhibitor MDM2. GATA2 and RASSF4 are anti-correlated in human cell lines and AML patient cell bulk and single cell expression datasets. Knockdown of Rassf4 in Gata2 low cells resulted in doxorubicin or nutlin-3 resistance. Conversely, overexpression of Rassf4 results in sensitization of cells expressing high levels of Gata2. Finally, doxorubicin and nutlin-3 are synergistic in Gata2-high murine AML, as well as AML patient samples. We discovered a previously unappreciated role for GATA2 in dampening p53-mediated apoptosis via transcriptional regulation of RASSF4, a modulator of MDM2. This role for GATA2 directly links the expression of a stemness associated transcription factor to chemotherapy resistance.","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142999660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

NETs persisting in vasculature undergo self-renewal with consequences for subsequent infection: a mouse model study.

IF 21 1区医学

Blood Pub Date : 2025-01-22 DOI: 10.1182/blood.2024026643

Michal Santocki, Anna Such, Dominika Drab, Gabriela Burczyk, Elzbieta Kolaczkowska

{"title":"NETs persisting in vasculature undergo self-renewal with consequences for subsequent infection: a mouse model study.","authors":"Michal Santocki, Anna Such, Dominika Drab, Gabriela Burczyk, Elzbieta Kolaczkowska","doi":"10.1182/blood.2024026643","DOIUrl":"https://doi.org/10.1182/blood.2024026643","url":null,"abstract":"While key for pathogen immobilization, neutrophil extracellular traps (NETs) often cause severe bystander cell/tissue damage. This was hypothesized to depend on their prolonged presence in the vasculature, leading to cytotoxicity. Imaging of NETs (histones, neutrophil elastase, extracellular DNA) with intravital microscopy in blood vessels of mouse livers in a pathogen-replicative-free environment (endotoxemia) led to detection of NET proteins attached to the endothelium for months despite the early disappearance of extracellular DNA. Intravascular liver macrophages (Kupffer cells) and neutrophils, but not monocytes, were involved in NET removal. They utilized scavenger receptors (SR-A) and Toll-like receptors (TLR2/4) to recognize NET components. Despite the absence of further stimuli, 14 days later a second wave of NET formation occurred, initiated by remnants of NETs from the first wave. The second burst of NET production was triggered by histones, which induced an inflammatory milieu (IL-1β) and activated platelets and coagulation-related events, including factor VII-activating protease (FSAP) activity. This in turn recruited and activated neutrophils to release the second wave of NETs. In peptidyl arginine deiminase (PAD4)-deficient mice, not forming NETs, inflammation and liver damage were reduced in comparison to their wild-type counterparts. When mice were challenged with methicillin-resistant Staphylococcus aureus (MRSA) 14 or 165 days post the second NETs, the course of infection/injury was diminished and exacerbated, respectively. Our study demonstrates that the complete removal of NETs in vivo takes much longer than hypothesized, and a vicious cycle of NET formation/disassembly impacts subsequent infection, depending on the time elapsed since its occurrence.","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142999766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Two-layered immune escape in AML is overcome by Fcγ receptor activation and inhibition of PGE2 signaling in NK cells.

IF 21 1区医学

Blood Pub Date : 2025-01-21 DOI: 10.1182/blood.2024025706

Charlotte Rothfuß, Tobias Baumann, Sainitin Donakonda, Bettina Brauchle, Anetta Marcinek, Christian Urban, Julia Mergner, Anna-Marie Pedde, Anna Hirschberger, Christina Krupka, Anne-Sophie Neumann, Gerulf Hänel, Camilla Merten, Rupert Öllinger, Judith S Hecker, Tanja Bauer, Christian Rudolf Schmid, Katharina S Götze, Jennifer Altomonte, Veit L Bücklein, Roland Jacobs, Roland Rad, Corinna Dawid, Luca Simeoni, Burkhart Schraven, Andreas Pichlmair, Marion Subklewe, Percy Alexander Knolle, Jan P Böttcher, Bastian Höchst

{"title":"Two-layered immune escape in AML is overcome by Fcγ receptor activation and inhibition of PGE2 signaling in NK cells.","authors":"Charlotte Rothfuß, Tobias Baumann, Sainitin Donakonda, Bettina Brauchle, Anetta Marcinek, Christian Urban, Julia Mergner, Anna-Marie Pedde, Anna Hirschberger, Christina Krupka, Anne-Sophie Neumann, Gerulf Hänel, Camilla Merten, Rupert Öllinger, Judith S Hecker, Tanja Bauer, Christian Rudolf Schmid, Katharina S Götze, Jennifer Altomonte, Veit L Bücklein, Roland Jacobs, Roland Rad, Corinna Dawid, Luca Simeoni, Burkhart Schraven, Andreas Pichlmair, Marion Subklewe, Percy Alexander Knolle, Jan P Böttcher, Bastian Höchst","doi":"10.1182/blood.2024025706","DOIUrl":"https://doi.org/10.1182/blood.2024025706","url":null,"abstract":"Loss of anticancer NK cell function in AML patients is associated with fatal disease progression and remains poorly understood. Here, we demonstrate that AML-blasts isolated from patients rapidly inhibit NK cell function and escape NK cell-mediated killing. Transcriptome analysis of NK cells exposed to AML-blasts revealed increased CREM expression and transcriptional activity, indicating enhanced cAMP signalling, confirmed by uniform production of the cAMP-inducing prostanoid PGE2 by all AML-blast isolates from patients. Phosphoproteome analysis disclosed that PGE2 induced a blockade of LCK-ERK signalling that is crucial for NK cell activation, indicating a two-layered escape of AML-blasts with low expression of NK cell-activating ligands and inhibition of NK cell signalling. To evaluate the therapeutic potential to target PGE2 inhibition, we combined Fcg-receptor-mediated activation with the prevention of inhibitory PGE2-signalling. This rescued NK cell function and restored the killing of AML-blasts. Thus, we identify the PGE2-LCK signalling axis as the key barrier for NK cell activation in two-layered immune escape of AML-blasts that can be targeted for immune therapy to reconstitute anti-cancer NK cell immunity in AML patients.","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142999767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Daratumumab for maintenance in myeloma.

IF 21 1区医学

Blood Pub Date : 2025-01-16 DOI: 10.1182/blood.2024026888

Cyrille Touzeau, Aurore Perrot

引用次数: 0

B-1 B cells lose self-control in SCD.

IF 20.3 1区医学

Blood Pub Date : 2025-01-16 DOI: 10.1182/blood.2024026549

David R Gibb,Sean R Stowell

引用次数: 0

Combined targeted modality in cHL: a risky bet?

IF 20.3 1区医学

Blood Pub Date : 2025-01-16 DOI: 10.1182/blood.2024027360

Paul J Bröckelmann,Bastian von Tresckow

引用次数: 0

HLA-I aberrations in cutaneous T-cell lymphoma.

IF 20.3 1区医学

Blood Pub Date : 2025-01-16 DOI: 10.1182/blood.2024027135

Ting Zhou,Kojo S J Elenitoba-Johnson

引用次数: 0

Brentuximab vedotin and nivolumab for cHL.

IF 20.3 1区医学

Blood Pub Date : 2025-01-16 DOI: 10.1182/blood.2024027957

引用次数: 0

Is it time to screen for multiple myeloma?

IF 20.3 1区医学

Blood Pub Date : 2025-01-16 DOI: 10.1182/blood.2024027065

Irene M Ghobrial,Floris Chabrun

引用次数: 0

Defining 2 Biologically and Clinically Distinct Groups in Acute Leukemia with a Mixed Phenotype.

IF 20.3 1区医学

Blood Pub Date : 2025-01-15 DOI: 10.1182/blood.2024026273

Pallavi Galera,Deepika Dilip,Andriy Derkach,Alexander Chan,Yanming Zhang,Sonali Persaud,Tanmay Mishra,Kyle Kramer,Mahak Kathpalia,Ying Liu,Christopher A Famulare,Qi Gao,Douglas Alexander Mata,Maria E Arcila,Mark B Geyer,Eytan M Stein,Ahmet Dogan,Mikhail Roshal,Ross L Levine,Jacob L Glass,Wenbin Xiao

{"title":"Defining 2 Biologically and Clinically Distinct Groups in Acute Leukemia with a Mixed Phenotype.","authors":"Pallavi Galera,Deepika Dilip,Andriy Derkach,Alexander Chan,Yanming Zhang,Sonali Persaud,Tanmay Mishra,Kyle Kramer,Mahak Kathpalia,Ying Liu,Christopher A Famulare,Qi Gao,Douglas Alexander Mata,Maria E Arcila,Mark B Geyer,Eytan M Stein,Ahmet Dogan,Mikhail Roshal,Ross L Levine,Jacob L Glass,Wenbin Xiao","doi":"10.1182/blood.2024026273","DOIUrl":"https://doi.org/10.1182/blood.2024026273","url":null,"abstract":"A mixed phenotype is characteristic of de novo Mixed Phenotype Acute Leukemia (MPAL) but can also be seen in other leukemias. It poses substantial classification and management dilemmas. Herein, we report a large cohort of acute leukemia with a mixed phenotype and define Acute Myeloid Leukemia with Mixed Phenotype (AML-MP) and MPAL as two distinct groups by characterizing the clinical, genetic, and transcriptomic features. Clinically, patients with AML-MP and MPAL were both treated with either AML- or acute lymphoblastic leukemia (ALL)-directed induction regimens. AML-MP shows inferior responses (HR, 12.5; 95% CI, 2.72-57.8; p=.001), while MPAL shows better responses to ALL-directed treatment. Genetically, AML-MP harbors more frequent RUNX1 (23/52, 44%) and TP53 (12/52, 23.1%) mutations. In contrast, RUNX1 mutations are less frequent in MPAL (8/35, 23%, p=.01 vs AML-MP) and TP53 mutations as a driver are virtually absent in MPAL. Transcriptionally, AML-MP shows enrichment for stemness signatures, and a relative deficit of transcription factors critical for myeloid and lymphoid differentiation. Furthermore, AML-MP rarely switches to a lymphoid immunophenotype after treatment, in contrast to MPAL (1/40, 2.5%, vs. 10/28, 35.7%, p=.0003). Lastly, a genomic classification framework is proposed for future studies. Together, these data support the designation of AML-MP as a diagnosis distinct from MPAL and provide novel insights into the pathogenesis and therapies of acute leukemia with a mixed phenotype.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"30 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142988650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0