IF 21 1区医学

Blood Pub Date : 2025-03-27 DOI: 10.1182/blood.2024024130

Qi Han, Yan Gu, Huimin Xiang, Linyao Zhang, Yan Wang, Chan Yang, Jun Li, Chelsea Steiner, Rosa Lapalombella, Jennifer A Woyach, Yiping Yang, Sinisa Dovat, Chunhua Song, Zheng Ge

{"title":"Targeting WDR5/ATAD2 signaling by the CK2/IKAROS axis demonstrates therapeutic efficacy in T-ALL.","authors":"Qi Han, Yan Gu, Huimin Xiang, Linyao Zhang, Yan Wang, Chan Yang, Jun Li, Chelsea Steiner, Rosa Lapalombella, Jennifer A Woyach, Yiping Yang, Sinisa Dovat, Chunhua Song, Zheng Ge","doi":"10.1182/blood.2024024130","DOIUrl":"10.1182/blood.2024024130","url":null,"abstract":"Abstract: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with a poor prognosis and limited options for targeted therapies. Identifying new molecular targets to develop novel therapeutic strategies is the pressing immediate issue in T-ALL. Here, we observed high expression of WD repeat-containing protein 5 (WDR5) in T-ALL. With in vitro and in vivo models, we demonstrated the oncogenic role of WDR5 in T-ALL by activating cell cycle signaling through its new downstream effector, ATPase family AAA domain-containing 2 (ATAD2). Moreover, the function of a zinc finger transcription factor of the Kruppel family (IKAROS) is often impaired by genetic alteration and casein kinase II (CK2) which is overexpressed in T-ALL. We found that IKAROS directly regulates WDR5 transcription; CK2 inhibitor, CX-4945, strongly suppresses WDR5 expression by restoring IKAROS function. Last, combining CX-4945 with WDR5 inhibitor demonstrates synergistic efficacy in the patient-derived xenograft mouse models. In conclusion, our results demonstrated that WDR5/ATAD2 is a new oncogenic signaling pathway in T-ALL, and simultaneous targeting of WRD5 and CK2/IKAROS has synergistic antileukemic efficacy and represents a promising potential strategy for T-ALL therapy.","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1407-1421"},"PeriodicalIF":21.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11969266/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142944653","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}

引用次数: 0

PGE2 inhibition to prevent AML escape from NK cells.

IF 21 1区医学

Blood Pub Date : 2025-03-27 DOI: 10.1182/blood.2024027931

Federico Simonetta

引用次数: 0

Two is better than one: dual targeting of WDR5 in T-ALL.

IF 21 1区医学

Blood Pub Date : 2025-03-27 DOI: 10.1182/blood.2024027633

Alexander A Wurm, Denis M Schewe

引用次数: 0

Warthin-Finkeldey cells seen in a setting other than measles: chronic lymphocytic leukemia/small lymphocytic lymphoma.

IF 21 1区医学

Blood Pub Date : 2025-03-27 DOI: 10.1182/blood.2024028017

Tanner J Bakhshi, Sergio Pina-Oviedo

引用次数: 0

Atypical chronic myeloid leukemia: from cytology to molecular characterization.

IF 21 1区医学

Blood Pub Date : 2025-03-27 DOI: 10.1182/blood.2024027505

Aida Calo-Pérez, Raquel Martínez-Fernández

引用次数: 0

How I diagnose and treat acute infection-associated purpura fulminans. 如何诊断和治疗急性感染相关性暴发性紫癜。

IF 21 1区医学

Blood Pub Date : 2025-03-27 DOI: 10.1182/blood.2024025078

Pavan K Bendapudi, Julie-Aurore Losman

{"title":"How I diagnose and treat acute infection-associated purpura fulminans.","authors":"Pavan K Bendapudi, Julie-Aurore Losman","doi":"10.1182/blood.2024025078","DOIUrl":"10.1182/blood.2024025078","url":null,"abstract":"Abstract: Purpura fulminans (PF) is a rare but devastating complication of sepsis characterized by a highly thrombotic subtype of disseminated intravascular coagulation (DIC). A medical emergency, PF often requires the involvement of consultant hematologists to assist with diagnosis and management of patients who are in a highly dynamic and deteriorating clinical situation. Patients who survive past the first 24 to 72 hours often die from complications of unchecked thrombosis rather than shock, and survivors are usually left with severe scarring and tissue loss. Despite these challenging features, PF is a pathophysiologically distinct, homogeneous, and highly predictable form of sepsis-associated DIC for which poor outcomes are not a foregone conclusion. The fundamental pathologic lesion in PF is a failure of the anticoagulant protein C pathway, which leads to uncontrolled microvascular clotting and inadequate protein C-mediated cytoprotective effects, which are vital for survival in sepsis. Herein, we review the clinical features and diagnosis of PF. Drawing from existing clinical literature and recent advances in our understanding of the pathophysiology of PF, we describe rationally designed treatment approaches for this disorder, including repletion of natural circulating anticoagulants, use of therapeutic anticoagulation, and ways to optimize transfusion support, and we outline specific interventions that we would recommend avoiding.","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1358-1368"},"PeriodicalIF":21.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142944639","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

Sickle cell trait does not cause "sickle cell crisis" leading to exertion-related death: a systematic review.

IF 21 1区医学

Blood Pub Date : 2025-03-27 DOI: 10.1182/blood.2024026899

Lachelle D Weeks, Allecia M Wilson, Rakhi P Naik, Yvonne Efebera, M Hassan Murad, Anjlee Mahajan, Patrick T McGann, Madeleine Verhovsek, Angela C Weyand, Ahmar U Zaidi, Michael R DeBaun, Chancellor Donald, Roger A Mitchell

{"title":"Sickle cell trait does not cause \"sickle cell crisis\" leading to exertion-related death: a systematic review.","authors":"Lachelle D Weeks, Allecia M Wilson, Rakhi P Naik, Yvonne Efebera, M Hassan Murad, Anjlee Mahajan, Patrick T McGann, Madeleine Verhovsek, Angela C Weyand, Ahmar U Zaidi, Michael R DeBaun, Chancellor Donald, Roger A Mitchell","doi":"10.1182/blood.2024026899","DOIUrl":"10.1182/blood.2024026899","url":null,"abstract":"Abstract: Globally, an estimated 300 million individuals have sickle cell trait (SCT), the carrier state for sickle cell disease (SCD). Although SCD is associated with increased morbidity and shortened life span, SCT has a life span comparable with that of the general population. However, \"sickle cell crisis\" has been used as a cause of death for decedents with SCT in reports of exertion-related death in athletes, military personnel, and individuals in police custody. To appraise this practice, the American Society of Hematology convened an expert panel of hematologists and forensic pathologists to conduct a systematic review of the literature relating to the occurrence of sickle cell pain crises and exertion-related mortality in people with SCT. Multiple bibliographic databases were searched with controlled vocabulary and keywords related to \"sickle cell trait,\" \"vaso-occlusive pain,\" and \"death,\" yielding 18 of 1474 citations. Independent pairs of reviewers selected studies and extracted data. We found no studies comparing uncomplicated acute pain crises in individuals with SCT and SCD. Additionally, no study was identified to support the occurrence of acute vaso-occlusive pain crises in individuals with SCT. Furthermore, this systematic review did not identify any evidence to support an association between SCT and sudden unexplained death in the absence of exertion-related rhabdomyolysis. We conclude that there are no data to support the diagnosis of acute vaso-occlusive sickle cell crisis as a cause of death in SCT, nor does the available evidence support the use of SCT as a cause of exertion-related death without rhabdomyolysis.","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1345-1352"},"PeriodicalIF":21.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063656","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

Jumping barriers in clinical trials: release the brake.

IF 21 1区医学

Blood Pub Date : 2025-03-27 DOI: 10.1182/blood.2024027711

Lionel Adès

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. AML的双层免疫逃逸是通过激活Fcγ受体和抑制NK细胞中的PGE2信号来克服的。

IF 21 1区医学

Blood Pub Date : 2025-03-27 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 Schmid, Katharina S Götze, Jennifer Altomonte, Veit Bücklein, Roland Jacobs, Roland Rad, Corina Dawid, Luca Simeoni, Burkhart Schraven, Andreas Pichlmair, Marion Subklewe, Percy A 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 Schmid, Katharina S Götze, Jennifer Altomonte, Veit Bücklein, Roland Jacobs, Roland Rad, Corina Dawid, Luca Simeoni, Burkhart Schraven, Andreas Pichlmair, Marion Subklewe, Percy A Knolle, Jan P Böttcher, Bastian Höchst","doi":"10.1182/blood.2024025706","DOIUrl":"10.1182/blood.2024025706","url":null,"abstract":"Abstract: Loss of anticancer natural killer (NK) cell function in patients with acute myeloid leukemia (AML) 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 cyclic adenosine monophosphate (cAMP) signaling, confirmed by uniform production of the cAMP-inducing prostanoid prostaglandin E2 (PGE2) by all AML-blast isolates from patients. Phosphoproteome analysis disclosed that PGE2 induced a blockade of lymphocyte-specific protein tyrosine kinase (LCK)-extracellular signal-regulated kinase signaling that is crucial for NK cell activation, indicating a 2-layered escape of AML blasts with low expression of NK cell-activating ligands and inhibition of NK cell signaling. To evaluate the therapeutic potential to target PGE2 inhibition, we combined Fcγ-receptor-mediated activation with the prevention of inhibitory PGE2 signaling. This rescued NK cell function and restored the killing of AML blasts. Thus, we identify the PGE2-LCK signaling axis as the key barrier for NK cell activation in 2-layered immune escape of AML blasts that can be targeted for immune therapy to reconstitute anticancer NK cell immunity in patients with AML.","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1395-1406"},"PeriodicalIF":21.0,"publicationDate":"2025-03-27","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

Impact of new medications on the treatment of immune TTP.

IF 21 1区医学

Blood Pub Date : 2025-03-27 DOI: 10.1182/blood.2024026390

Marie Scully, Lara Howells, William A Lester

引用次数: 0

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