journal
https://read.qxmd.com/read/37774374/spatial-mapping-of-human-hematopoiesis-at-single-cell-resolution-reveals-aging-associated-topographic-remodeling
#1
JOURNAL ARTICLE
Aleksandr Sarachakov, Arina Varlamova, Viktor Svelolkin, Margarita Polyakova, Itzel Valencia, Caitlin Unkenholz, Tania Pannellini, Ilia Galkin, Pavel Ovcharov, Dmitry Tabakov, Ekaterina Postovalova, Nara Shin, Isha Sethi, Alexander Bagaev, Tomer Itkin, Genevieve M Crane, Michael J Kluk, Julia T Geyer, Giorgio Ga Inghirami, Sanjay S Patel
The spatial anatomy of hematopoiesis in bone marrow has been extensively studied in mice and other preclinical models, but technical challenges have precluded a commensurate exploration in humans. Institutional pathology archives contain thousands of paraffinized bone marrow core biopsy tissue specimens, providing a rich resource for studying the intact human bone marrow topography in a variety of physiologic states. Thus, we developed an end-to-end pipeline involving multiparameter whole tissue staining, in situ imaging at single-cell resolution, and artificial intelligence (AI)-based digital Whole Slide Image (WSI) analysis, and then applied it to a cohort of disease-free samples to survey alterations in the hematopoietic topography associated with aging...
September 29, 2023: Blood
https://read.qxmd.com/read/37774372/diagnosis-and-classification-of-myelodysplastic-syndromes
#2
JOURNAL ARTICLE
Robert P Hasserjian, Ulrich Germing, Luca Malcovati
Myelodysplastic syndromes (MDSs) are neoplastic myeloid proliferations characterized by ineffective hematopoiesis resulting in peripheral blood cytopenias. MDS is distinguished from non-neoplastic clonal myeloid proliferations by the presence of morphologic dysplasia and from acute myeloid leukemia (AML) by a blast threshold of 20%. The diagnosis of MDS can be challenging due to the myriad other causes of cytopenias: accurate diagnosis requires the integration of clinical features with bone marrow and peripheral blood morphology, immunophenotyping, and genetic testing...
September 29, 2023: Blood
https://read.qxmd.com/read/37774369/cold-exposure-induces-vaso-occlusion-and-pain-in-sickle-mice-that-depend-on-complement-activation
#3
JOURNAL ARTICLE
Zalaya K Ivy, John D Belcher, Iryna A Khasabova, Chunsheng Chen, Joseph P Juliette, Fuad R Abdulla, Conglin Ruan, Kaje Allen, Julia Nguyen, Victoria M Rogness, Joan D Beckman, Sergey G Khasabov, Kalpna Gupta, Ronald P Taylor, Donald A Simone, Gregory M Vercellotti
Vaso-occlusive pain episodes (VOE) cause severe pain in sickle cell disease (SCD) patients. Vaso-occlusive events promote ischemia/reperfusion (I/R) pathobiology that activates complement. We hypothesized that complement activation is linked to VOE. We used cold to induce VOE in the Townes sickle (HbSS) mouse model and complement inhibitors to determine whether anaphylatoxin C5a mediates VOE. We used a dorsal skinfold chamber to measure microvascular stasis (vaso-occlusion) and von Frey filaments applied to the plantar surface of the hind paw to assess mechanical hyperalgesia in HbSS and control (HbAA) mice after cold-exposure (10oC/50oF) for 1 hour...
September 29, 2023: Blood
https://read.qxmd.com/read/37756525/germline-variant-gfi1-36n-affects-dna-repair-and-sensitizes-aml-cells-to-dna-damage-and-repair-therapy
#4
JOURNAL ARTICLE
Daria Frank, Pradeep Kumar Patnana, Jan Vorwerk, Lianghao Mao, Lavanya Mokada Gopal, Noelle Jung, Thorben Hennig, Leo Ruhnke, Joris Maximillian Frenz, Maithreyan Kuppusamy, Robert J Autry, Lanying Wei, Kaiyan Sun, Helal Ahmed, Axel Künstner, Hauke Busch, Heiko Müller, Stephan Hutter, Gregor Hoermann, Longlong Liu, Xiaoqing Xie, Yahya Al-Matary, Subbaiah Chary Nimmagadda, Fiorella Charles Cano, Michael Heuser, Felicitas R Thol, Gudrun Göhring, Doris Steinemann, Jürgen Thomale, Theo Leitner, Anja Fischer, Roland Rad, Christoph Röllig, Heidi Altmann, Desiree Kunadt, Wolfgang E Berdel, Jana Hüve, Felix Neumann, Jürgen Klingauf, Virginie Calderon, Bertram Opalka, Ulrich Dührsen, Frank Rosenbauer, Martin Dugas, Julian Varghese, H Christian H Reinhardt, Nikolas von Bubnoff, Tarik Möröy, Georg Lenz, Aarif M N Batcha, Marianna Giorgi, Murugan Selvam, Eunice S Wang, Shannon K McWeeney, Jeffrey W Tyner, Friedrich Stölzel, Matthias Mann, Ashok Kumar Jayavelu, Cyrus Khandanpour
Growth Factor Independence 1 (GFI1) is a DNA-binding transcription factor and a key regulator of haematopoiesis. GFI1-36N is a germline variant causing a change of serine (S) to asparagine (N) at position 36. We previously reported that the GFI1-36N allele has a prevalence of 10-15% among patients with acute myeloid leukemia (AML) and 5-7% among healthy Caucasians and promotes the development of this disease. Using a multi-omics approach, we show here that GFI1-36N expression is associated with increased frequencies of chromosomal aberrations, mutational burden and mutational signatures in both murine and human AML and impedes homologous recombination-directed (HR) DNA repair in leukemic cells...
September 26, 2023: Blood
https://read.qxmd.com/read/37756522/a-human-genome-editing-based-mll-af4-b-cell-all-model-recapitulates-key-cellular-and-molecular-leukemogenic-features
#5
JOURNAL ARTICLE
Clara Bueno, Raul Torres-Ruíz, Talia Velasco-Hernandez, Oscar Molina, Paolo Petazzi, Alba Martinez-Moreno, Virginia Carolina Rodríguez-Cortez, Meritxell Vinyoles, Sandra Cantilena, Owen Williams, Nerea Vega-García, Sandra Rodriguez-Perales, José Carlos Segovia, Oscar Quintana-Bustamante, Anindita Roy, Claus Meyer, Rolf Marschalek, Alastair Smith, Thomas A Milne, Mario F Fraga, Juan Ramón Ramón Tejedor, Pablo Menendez
The cellular ontogeny and location of the MLL-breakpoint influence the capacity of MLL-edited CD34+ HSPCs to initiate pro-B-ALL, and recapitulate the molecular features of MLL-AF4+ infant B-ALL patients. We provide key insights into the cellular-molecular leukemogenic determinants of MLL-AF4+ infant B-ALL.
September 26, 2023: Blood
https://read.qxmd.com/read/37748139/aging-disturbed-fus-phase-transition-impairs-hematopoietic-stem-cell-by-altering-chromatin-structure
#6
JOURNAL ARTICLE
Baixue Tang, Xinming Wang, Hanqing He, Ruiqing Chen, Guofeng Qiao, Yang Yang, Zihan Xu, Longteng Wang, Qiongye Dong, Jia Yu, Michael Zhang, Minglei Shi, Jianwei Wang
Aged hematopoietic stem cells (HSCs) exhibit compromised reconstitution capacity. While, the molecular mechanisms behind this phenomenon are not fully understood. In this study, we observed that the expression of FUS is increased in aged HSCs and enforced FUS recapitulates the phenotype of aged HSCs through RGG-mediated aberrant FUS phase transition. By utilizing Fus-gfp mice, we observed that FUShigh HSCs exhibit compromised FUS mobility and resemble aged HSCs both functionally and transcriptionally. The percentage of FUShigh HSCs is increased upon physiological aging and replication stress, and FUSlow HSCs of aged mice exhibit youthful function...
September 25, 2023: Blood
https://read.qxmd.com/read/37748137/elevated-serum-tarc-levels-precede-classic-hodgkin-lymphoma-diagnosis-by-several-years
#7
JOURNAL ARTICLE
Arjan Diepstra, Ilja M Nolte, Anke van den Berg, Larry I Magpantay, Otoniel Martinez-Maza, Lynn I Levin
Tumor cells in classic Hodgkin lymphoma produce high quantities of the chemokine TARC. We measured TARC levels in pre-diagnostic serum samples and found strikingly increased values in the vast majority of patients, up to over six years before diagnosis.
September 25, 2023: Blood
https://read.qxmd.com/read/37738655/tcr%C3%AE-%C3%AE-cd19-cell-depleted-hla-haploidentical-transplantation-to-treat-pediatric-acute-leukemia-updated-final-analysis
#8
JOURNAL ARTICLE
Pietro Merli, Mattia Algeri, Federica Galaverna, Valentina Bertaina, Barbarella Lucarelli, Emilia Boccieri, Marco Becilli, Francesco Quagliarella, Chiara Rosignoli, Simone Biagini, Elia Girolami, Antonella Meschini, Giovanna Del Principe, Raffaella Sborgia, Maria Luigia Catanoso, Roberto Carta, Luisa Strocchio, Rita Maria Pinto, Barbara Buldini, Michela Falco, Raffaella Meazza, Daniela Pende, Marco Andreani, Giuseppina Li Pira, Daria Pagliara, Franco Locatelli
TCRαβ/CD19-cell depletion is a promising graft manipulation technique frequently used in the context of HLA-haploidentical hematopoietic stem cell transplantation (HSCT). We previously reported the results of a phase I-II clinical trial (NCT01810120) to assess the safety and the efficacy of this type of ex-vivo T cell-depletion in 80 children with acute leukemia, showing promising survival outcomes. We now report an updated analysis on a cohort of 213 children with a longer follow-up (median value of 47...
September 22, 2023: Blood
https://read.qxmd.com/read/37738652/egr1-mediated-metabolic-reprogramming-to-oxidative-phosphorylation-contributes-to-ibrutinib-resistance-in-b-cell-lymphoma
#9
JOURNAL ARTICLE
Yunxia Liu, Shuichi Kimpara, Nguyet-Minh M Hoang, Anusara Daenthanasanmak, Yangguang Li, Li Lu, Vu N Ngo, Paul Bates, Longzhen Song, Xiaoyue Gao, Samantha Bebel, Madelyn Chen, Ruoyu Chen, Xiyu Zhang, Paul E Selberg, Vaishalee P Kenkre, Christian M Capitini, Thomas Waldmann, Lixin Rui
The use of Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib to block B cell receptor (BCR) signaling has achieved a remarkable clinical response in several B cell malignancies including mantle cell lymphoma (MCL) and diffuse large B cell lymphoma (DLBCL). Acquired drug resistance, however, is significant and impacts long-term survival of these patients. Here we demonstrate that the transcription factor EGR1 is involved in ibrutinib resistance. We found that EGR1 expression is elevated in ibrutinib-resistant activated B-cell-like subtype (ABC) DLBCL and MCL cells and can be further upregulated upon ibrutinib treatment...
September 22, 2023: Blood
https://read.qxmd.com/read/37738633/reinforced-anti-myeloma-therapy-via-dual-lymphoid-activation-mediated-by-a-panel-of-antibodies-armed-with-bridging-bite
#10
JOURNAL ARTICLE
Tatsuya Konishi, Toshiki Ochi, Masaki Maruta, Kazushi Tanimoto, Yukihiro Miyazaki, Chika Iwamoto, Takashi Saitou, Takeshi Imamura, Masaki Yasukawa, Katsuto Takenaka
Immunotherapy using bispecific antibodies including bispecific T-cell engager (BiTE) has the potential to enhance the efficacy of treatment for relapsed/refractory multiple myeloma. However, myeloma may still recur after treatment due to downregulation of a target antigen and/or myeloma cell heterogeneity. To strengthen immunotherapy for myeloma while overcoming its characteristics, we have newly developed a BiTE-based modality, referred to as Bridging-BiTE (B-BiTE). B-BiTE was able to bind to both a human IgG-Fc domain and the CD3 molecule...
September 22, 2023: Blood
https://read.qxmd.com/read/37738626/natural-history-study-of-patients-with-familial-platelet-disorder-with-myeloid-malignancy
#11
JOURNAL ARTICLE
Paul P Liu, Lea Cunningham, Matthew Douglas Merguerian, Katherine R Calvo, Joie Davis, Natalie T Deuitch, Alina E Dulau-Florea, Nisha Patel, Kai Yu, Keith Sacco, Sumona Bhattacharya, Monica Passi, Neval Ozkaya, Seila Vanessa De Leon, Shawn Nathan Chong, Kathleen Marie Craft, Jamie L Diemer, Erica Bresciani, Kevin J O'Brien, Elizabeth J Andrews, Nguyen Park, Londa Hathaway, Edward W Cowen, Theo Heller, Kerry Ryan, Amisha Barochia, Khanh Nghiem, Julie E Niemela, Sergio D Rosenzweig, David J Young, Pamela Frischmeyer-Guerrerio, Raul C Braylan
Deleterious germline RUNX1 variants cause the autosomal dominant disease familial platelet disorder with associated myeloid malignancy (FPDMM), characterized by thrombocytopenia, platelet functional defects and predisposition to hematologic malignancies (HMs). We launched a FPDMM natural history study and, from January 2019-December 2021, enrolled 214 participants, including 111 patients with 39 different RUNX1 variants from 45 unrelated families. Of those with available data, 91% (70/77) had thrombocytopenia, 100% (18/18) had abnormal platelet aggregometry, 46% (16/35) had platelets with decreased dense granules, and 51% (28/55) had abnormal bleeding scores...
September 22, 2023: Blood
https://read.qxmd.com/read/37738563/tafasitamab-and-lenalidomide-in-large-b-cell-lymphoma-real-world-outcomes-in-a-multicenter-retrospective-study
#12
JOURNAL ARTICLE
David A Qualls, Nicholas Lambert, Paolo F Caimi, Mwanasha H Merrill, Priyanka Pullarkat, Richard C Godby, David A Bond, Graham T Wehmeyer, Jason T Romancik, Behzad Amoozgar, Lori A Leslie, Loretta J Nastoupil, Jennifer L Crombie, Jeremy S Abramson, Arushi Khurana, Grzegorz S Nowakowski, Kami J Maddocks, Sarah C Rutherford, Brad S Kahl, Michelle Okwali, Michael J Buege, Venkatraman E Seshan, Connie L Batlevi, Gilles A Salles
In this real-world evaluation of tafasitamab-lenalidomide (TL) in relapsed/refractory LBCL, patients receiving TL had higher rates of comorbidities and high-risk disease characteristics, and substantially lower progression-free survival and overall survival, compared to the L-MIND registration clinical trial for TL.
September 22, 2023: Blood
https://read.qxmd.com/read/37738562/loss-of-function-of-ent3-drives-histiocytosis-and-inflammation-through-tlr-mapk-signaling
#13
JOURNAL ARTICLE
Ruth Shiloh, Ruth Lubin, Odeya David, Ifat Geron, Elimelech Okon, Idit Hazan, Marketa Zaliova, Gil Amarilyo, Yehudit Birger, Yael Borovitz, Dafna Brik, Arnon Broides, Sarit Cohen-Kedar, Liora Harel, Eyal Kristal, Daria Kozlova, Galina Ling, Mika Shapira Rootman, Noa Shefer Averbuch, Shiri Spielman, Jan Trka, Shai Izraeli, Simon Yona, Sarah Elitzur
Histiocytoses are inflammatory myeloid neoplasms often driven by somatic activating mutations in mitogen-activated protein kinase (MAPK) cascade genes. H syndrome is an inflammatory genetic disorder caused by germline loss-of-function mutations in SLC29A3, encoding the lysosomal equilibrative nucleoside transporter 3 (ENT3). Patients with H syndrome are predisposed to develop histiocytosis, yet the mechanism is unclear. Here, through phenotypic, molecular and functional analysis of primary cells from a cohort of patients with H syndrome, we reveal the molecular pathway leading to histiocytosis and inflammation in this genetic disorder...
September 22, 2023: Blood
https://read.qxmd.com/read/37738561/hexim1-is-an-essential-transcription-regulator-during-human-erythropoiesis
#14
JOURNAL ARTICLE
Xiurui Lv, Kristin Murphy, Zachary Murphy, Michael Roger Getman, Nabil Fazleh Rahman, Yukio Nakamura, Lionel Blanc, Patrick G Gallagher, James Palis, Narla Mohandas, Laurie Ann Steiner
Regulation of RNA polymerase II (RNAPII) activity is an essential process that governs gene expression, however its contribution to the fundamental process of erythropoiesis remains unclear. HEXIM1 regulates RNAPII activity by controlling the location and activity of pTEFb (positive transcription factor beta). We identified a key role for HEXIM1 in controlling erythroid gene expression and function, with overexpression of HEXIM1 promoting erythroid proliferation and fetal globin expression. HEXIM1 regulated erythroid proliferation by enforcing RNAPII pausing at cell cycle check point genes and increasing RNAPII occupancy at genes that promote cycle progression...
September 22, 2023: Blood
https://read.qxmd.com/read/37738558/o-linked-sialic-acid-residues-on-platelet-membrane-glycoprotein-gp-iib-mask-the-human-hpa-9b-alloepitope
#15
JOURNAL ARTICLE
Nanyan Zhang, Mia J Sullivan, Brian R Curtis, Peter J Newman
Sialic acids occupy the terminal position of glycan chains and have the potential to influence the antigenicity of glycoproteins. The polymorphisms of Human Platelet Alloantigens (HPA)-3 and HPA-9, locating near the C-terminus of the extracellular domain of platelet membrane glycoprotein (GP)IIb, are adjacent to sialyl-Core 1 O-glycans emanating from serines 845 and 847. Whether the nearby O-glycans affect the antigenicity of HPA-9b, and/or influence the binding of anti-HPA-9b alloantibodies in clinically significant cases of neonatal alloimmune thrombocytopenia is unknown...
September 22, 2023: Blood
https://read.qxmd.com/read/37738460/inhibition-of-plk4-remodels-histone-methylation-and-activates-immune-response-via-cgas-sting-pathway-in-tp53-mutated-aml
#16
JOURNAL ARTICLE
Cheuk Him Man, Wing Lam, Chee Chean Dang, Xiao-Yuan Zeng, Li-Chuan Zheng, Natalie Nok-Man Chan, Nelson K L Ng, Koon-Chuen Chan, Tsz-Ho Kwok, Timothy Chi-Chun Ng, Wing Yan Leung, Michael Huen, Carmen Chak-Lui Wong, Chi Wai Eric So, Zhixun Dou, Susumu Goyama, Mark Robert Bray, Tak Wah Mak, Anskar Yu Hung Leung
Acute myeloid leukemia (AML) with TP53 mutation is one of the most lethal cancers and portends an extremely poor prognosis. Based on in silico analyses of druggable genes and differential gene expression in TP53 mutated AML, we identified polo-like kinase 4 (PLK4) as a novel therapeutic target and examined its expression, regulation, pathogenetic mechanisms and therapeutic potential in TP53 mutated AML. PLK4 expression was suppressed by activated p53 signaling in TP53 wildtype AML and was increased in TP53 mutated AML cell lines and primary samples...
September 22, 2023: Blood
https://read.qxmd.com/read/37729611/integrated-epigenetic-and-transcriptional-single-cell-analysis-of-t-11-14-multiple-myeloma-and-its-bcl2-dependency
#17
JOURNAL ARTICLE
Noémie Leblay, Sungwoo Ahn, Rémi Tilmont, Mansour Poorebrahim, Ranjan Maity, Holly Lee, Elie Barakat, Jean-Baptiste Alberge, Sarthak Sinha, Arzina Jaffer, Benjamin G Barwick, Lawrence H Boise, Nizar J Bahlis, Paola Neri
The translocation t(11;14) occurs in 20% of multiple myeloma (MM) patients and results in the upregulation of CCND1. Nearly two-thirds of t(11;14) MM cells are BCL2 primed and highly responsive to the oral BCL2 inhibitor venetoclax. While it is evident that this unique sensitivity to venetoclax depends on the BH3-proapoptotic protein priming of BCL2, the biology underlying t(11;14) MM dependency on BCL2 is poorly defined. Importantly, the epigenetic regulation of t(11;14) transcriptomes and its impact on gene regulation and clinical response to venetoclax remains elusive...
September 20, 2023: Blood
https://read.qxmd.com/read/37729609/moving-towards-disease-modification-in-polycythemia-vera
#18
JOURNAL ARTICLE
Jan Philipp Bewersdorf, Joan How, Lucia Masarova, Prithviraj Bose, Naveen Pemmaraju, John O Mascarenhas, Raajit K Rampal
Polycythemia vera (PV) belongs to the BCR-ABL1-negative myeloproliferative neoplasms and is characterized by activating mutations in JAK2 and clinically presents with erythrocytosis, variable degrees of systemic and vasomotor symptoms, and an increased risk of both thromboembolic events and progression to myelofibrosis and acute myeloid leukemia (AML). Treatment selection is based on a patient's age and a history of thrombosis with low-risk PV patients treated with therapeutic phlebotomy and aspirin alone, while cytoreductive therapy with either hydroxyurea or interferon (IFN)-α is added for high-risk disease...
September 20, 2023: Blood
https://read.qxmd.com/read/37704579/splenic-iron-decreases-without-change-in-volume-or-liver-parameters-during-luspatercept-therapy
#19
JOURNAL ARTICLE
Christopher C Denton, Sadanand Vodala, Saranya Veluswamy, Thomas C Hofstra, Thomas D Coates, John C Wood
Splenic iron decreased while liver iron was stable during luspatercept therapy in some thalassemic individuals. This suggests reduction of ineffective erythropoiesis changes organ distribution of iron and demonstrates that liver iron concentration alone may not accurately reflect total body iron. Clinical trials: BEYOND: NCT03342404; BELIEVE: NCT02604433.
September 13, 2023: Blood
https://read.qxmd.com/read/37702537/how-i-treat-secondary-cns-involvement-by-aggressive-lymphomas
#20
JOURNAL ARTICLE
Juan Pablo Alderuccio, Lakshmi Nayak, Kate Cwynarski
Secondary central nervous system lymphoma (SCNSL) is a rare but clinically challenging scenario with historically disappointing outcomes. SCNSL refers to lymphoma that has spread into the CNS concurrently with systemic disease, or CNS relapse during or after frontline immunochemotherapy, presenting with or without systemic lymphoma. Diffuse large B-cell lymphoma (DLBCL) denotes the most common entity but an increased incidence is observed in other histologies such as Burkitt lymphoma and mantle cell lymphoma...
September 13, 2023: Blood
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