keyword
https://read.qxmd.com/read/36945617/novel-scheme-for-defining-the-clinical-implications-of-tp53-mutations-in-myeloid-neoplasia
#21
Waled Bahaj, Tariq Kewan, Carmelo Gurnari, Arda Durmaz, Ben Ponvilawan, Ishani Pandit, Yasuo Kubota, Olisaemeka D Ogbue, Misam Zawit, Yazan Madanat, Taha Bat, Suresh K Balasubramanian, Hussein Awada, Ramsha Ahmed, Minako Mori, Manja Meggendorfer, Torsten Haferlach, Valeria Visconte, Jaroslaw P Maciejewski
Background: TP53 mutations ( TP53 MT ) occur in diverse genomic configurations. Particularly, biallelic inactivation is associated with poor overall survival in cancer. Lesions affecting only one allele might not be directly leukemogenic, questioning the presence of cryptic biallelic subclones in cases with dismal prognosis. Methods: We have collected clinical and molecular data of 7400 patients with myeloid neoplasms and applied a novel model to properly resolve the allelic configuration of TP53 MT and assess prognosis more precisely...
March 9, 2023: Research Square
https://read.qxmd.com/read/36940410/impact-of-tp53-on-outcome-of-patients-with-myelofibrosis-undergoing-hematopoietic-stem-cell-transplantation
#22
MULTICENTER STUDY
Nico Gagelmann, Anita Badbaran, Rachel B Salit, Thomas Schroeder, Carmelo Gurnari, Simona Pagliuca, Victoria Panagiota, Christina Rautenberg, Bruno Cassinat, Felicitas Thol, Christine Wolschke, Marie Robin, Michael Heuser, Marie-Thérèse Rubio, Jaroslaw P Maciejewski, Hans Christian Reinhardt, Bart L Scott, Nicolaus Kröger
TP53 mutations (TP53MTs) have been associated with poor outcomes in various hematologic malignancies, but no data exist regarding its role in patients with myelofibrosis undergoing hematopoietic stem cell transplantation (HSCT). Here, we took advantage of a large international multicenter cohort to evaluate the role of TP53MT in this setting. Among 349 included patients, 49 (13%) had detectable TP53MT, of whom 30 showed a multihit configuration. Median variant allele frequency was 20.3%. Cytogenetic risk was favorable (71%), unfavorable (23%), and very high (6%), with complex karyotype present in 36 patients (10%)...
June 8, 2023: Blood
https://read.qxmd.com/read/36926651/a-multimodal-analysis-of-genomic-and-rna-splicing-features-in-myeloid-malignancies
#23
JOURNAL ARTICLE
Arda Durmaz, Carmelo Gurnari, Courtney E Hershberger, Simona Pagliuca, Noah Daniels, Hassan Awada, Hussein Awada, Vera Adema, Minako Mori, Ben Ponvilawan, Yasuo Kubota, Tariq Kewan, Waled S Bahaj, John Barnard, Jacob Scott, Richard A Padgett, Torsten Haferlach, Jaroslaw P Maciejewski, Valeria Visconte
RNA splicing dysfunctions are more widespread than what is believed by only estimating the effects resulting by splicing factor mutations (SFMT ) in myeloid neoplasia (MN). The genetic complexity of MN is amenable to machine learning (ML) strategies. We applied an integrative ML approach to identify co-varying features by combining genomic lesions (mutations, deletions, and copy number), exon-inclusion ratio as measure of RNA splicing (percent spliced in, PSI), and gene expression (GE) of 1,258 MN and 63 normal controls...
March 17, 2023: IScience
https://read.qxmd.com/read/36720101/validation-of-the-molecular-international-prognostic-scoring-system-in-patients-with-myelodysplastic-syndromes
#24
JOURNAL ARTICLE
Tariq Kewan, Waled Bahaj, Arda Durmaz, Mai Mostafa Aly, Olisaemeka D Ogbue, Hetty E Carraway, Mikkael A Sekeres, Valeria Visconte, Carmelo Gurnari, Jaroslaw P Maciejewski
No abstract text is available yet for this article.
January 30, 2023: Blood
https://read.qxmd.com/read/36709353/outcome-prediction-in-myelodysplastic-neoplasm-undergoing-hematopoietic-cell-transplant-in-the-molecular-era-of-ipss-m
#25
LETTER
Carmelo Gurnari, Nico Gagelmann, Anita Badbaran, Hussein Awada, Danai Dima, Simona Pagliuca, Maud D'Aveni-Piney, Enrico Attardi, Maria Teresa Voso, Raffaella Cerretti, Christine Wolschke, Marie Thérèse Rubio, Jaroslaw P Maciejewski, Nicolaus Kröger
No abstract text is available yet for this article.
March 2023: Leukemia
https://read.qxmd.com/read/36668915/hepatitis-c-infection-associated-with-acquired-pure-red-cell-aplasia
#26
Destini Teague, Carmelo Gurnari, Hussein Awada, Jaroslaw P Maciejewski, Ibrahim Ibrahim, Taha Bat
Acquired pure red cell aplasia is a rare bone marrow failure disorder characterized by many underlying etiologies. The hallmark bone marrow feature is the near absence of erythroid precursors that otherwise exhibit normal cellularity, which has been attributed to both immune- and cellular-mediated mechanisms. Besides being merely speculative and considering the rarity of the disorder, the description of acquired pure red cell aplasia clinical associations represents a unique occasion to improve our current clinical knowledge of the disease, reveal clues on its pathogenesis, and guide therapeutic decisions...
December 22, 2022: Tropical Medicine and Infectious Disease
https://read.qxmd.com/read/36499220/comprehensive-transcriptomic-analysis-of-vista-in-acute-myeloid-leukemia-insights-into-its-prognostic-value
#27
JOURNAL ARTICLE
Simona Pagliuca, Carmelo Gurnari, Keman Zhang, Tariq Kewan, Waled Bahaj, Minako Mori, Ishani Nautiyal, Marie Thérèse Rubio, Francesca Ferraro, Jaroslaw P Maciejewski, Li Wang, Valeria Visconte
The V-domain Ig suppressor of T-cell activation (VISTA) has been recognized as a critical negative regulator of antitumor immune response and is gaining growing interest as a potential pharmacological target in immunotherapy. This molecule is highly expressed in hematopoietic stem cells and myeloid compartment, and it has been found upmodulated in acute myeloid leukemia (AML). However, VISTA-associated immune features are relatively unexplored in myeloid malignancies. Herein, we aimed to explore whether this immune checkpoint regulator could play a role in the generation of an immune escape environment in AML patients...
November 28, 2022: International Journal of Molecular Sciences
https://read.qxmd.com/read/36325893/genomics-improves-risk-stratification-of-adults-with-t-cell-acute-lymphoblastic-leukemia-patients-enrolled-in-measurable-residual-disease-oriented-trials
#28
JOURNAL ARTICLE
Celia González-Gil, Mireia Morgades, Thaysa Lopes, Francisco Fuster-Tormo, Jesús García-Chica, Ran Zhao, Pau Montesinos, Anna Torrent, Marina Diaz-Beya, Rosa Coll, Lourdes Hermosín, Santiago Mercadal, José González-Campos, Lurdes Zamora, Teresa Artola, Ferran Vall-Llovera, Mar Tormo, Cristina Gil-Cortés, Pere Barba, Andrés Novo, Jordi Ribera, Teresa Bernal, Paula López De Ugarriza, María-Paz Queipo, Pilar Martínez-Sánchez, Alicia Giménez, Teresa González-Martínez, Antonia Cladera, José Cervera, Rosa Fernández-Martín, María Ángeles Ardaiz, María Jesús Vidal, Ángela Baena, Nuria López-Bigas, Anna Bigas, Jaroslaw Maciejewski, Alberto Orfao, Josep Maria Ribera, Eulalia Genescà
Genetic information has been crucial to understand the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) at diagnosis and at relapse, but still nowadays has a limited value in a clinical context. Few genetic markers are associated with the outcome of T-ALL patients, independently of measurable residual disease (MRD) status after therapy. In addition, the prognostic relevance of genetic features may be modulated by the specific treatment used. We analyzed the genetic profile of 145 T-ALL patients by targeted deep sequencing...
November 3, 2022: Haematologica
https://read.qxmd.com/read/36322930/germ-line-ddx41-mutations-define-a-unique-subtype-of-myeloid-neoplasms
#29
JOURNAL ARTICLE
Hideki Makishima, Ryunosuke Saiki, Yasuhito Nannya, Sophia Korotev, Carmelo Gurnari, June Takeda, Yukihide Momozawa, Steve Best, Pramila Krishnamurthy, Tetsuichi Yoshizato, Yoshiko Atsuta, Yusuke Shiozawa, Yuka Iijima-Yamashita, Kenichi Yoshida, Yuichi Shiraishi, Yasunobu Nagata, Nobuyuki Kakiuchi, Makoto Onizuka, Kenichi Chiba, Hiroko Tanaka, Ayana Kon, Yotaro Ochi, Masahiro M Nakagawa, Rurika Okuda, Takuto Mori, Akinori Yoda, Hidehiro Itonaga, Yasushi Miyazaki, Masashi Sanada, Takayuki Ishikawa, Shigeru Chiba, Hisashi Tsurumi, Senji Kasahara, Carsten Müller-Tidow, Akifumi Takaori-Kondo, Kazuma Ohyashiki, Toru Kiguchi, Fumihiko Matsuda, Joop H Jansen, Chantana Polprasert, Piers Blombery, Yoichiro Kamatani, Satoru Miyano, Luca Malcovati, Torsten Haferlach, Michiaki Kubo, Mario Cazzola, Austin G Kulasekararaj, Lucy A Godley, Jaroslaw P Maciejewski, Seishi Ogawa
Germ line DDX41 variants have been implicated in late-onset myeloid neoplasms (MNs). Despite an increasing number of publications, many important features of DDX41-mutated MNs remain to be elucidated. Here we performed a comprehensive characterization of DDX41-mutated MNs, enrolling a total of 346 patients with DDX41 pathogenic/likely-pathogenic (P/LP) germ line variants and/or somatic mutations from 9082 MN patients, together with 525 first-degree relatives of DDX41-mutated and wild-type (WT) patients. P/LP DDX41 germ line variants explained ∼80% of known germ line predisposition to MNs in adults...
February 2, 2023: Blood
https://read.qxmd.com/read/36266327/significance-of-hereditary-gene-alterations-for-the-pathogenesis-of-adult-bone-marrow-failure-versus-myeloid-neoplasia
#30
JOURNAL ARTICLE
Yasuo Kubota, Misam Zawit, Jibran Durrani, Wenyi Shen, Waled Bahaj, Tariq Kewan, Ben Ponvilawan, Minako Mori, Manja Meggendorfer, Carmelo Gurnari, Thomas LaFramboise, Simone Feurstein, Mikkael A Sekeres, Valeria Visconte, Lucy A Godley, Torsten Haferlach, Jaroslaw P Maciejewski
Broader genetic screening has led to the growing recognition of the role of germline variants associated with adult bone marrow failure (BMF) and myeloid neoplasia (MN) not exclusively in children and young adults. In this study, we applied a germline variant panel to 3008 adult BMF and MN cases to assess the importance of germline genetics and its impact on disease phenotype and prognosis. In our cohort, up to 9.7% of BMF and 5.3% of MN cases carried germline variants. Our cohort also included heterozygous carriers of recessive traits, suggesting they contribute to the risk of BMF and MN...
December 2022: Leukemia
https://read.qxmd.com/read/36253429/molecular-landscape-of-immune-pressure-and-escape-in-aplastic-anemia
#31
JOURNAL ARTICLE
Simona Pagliuca, Carmelo Gurnari, Colin Hercus, Sébastien Hergalant, Niroshan Nadarajah, Adam Wahida, Laila Terkawi, Minako Mori, Weiyin Zhou, Valeria Visconte, Stephen Spellman, Shahinaz M Gadalla, Caiying Zhu, Ping Zhu, Torsten Haferlach, Jaroslaw P Maciejewski
Idiopathic aplastic anemia (IAA) pathophysiology is dominated by autoreactivity of human leukocyte antigen (HLA)-restricted T-cells against antigens presented by hematopoietic stem and progenitor cells (HSPCs). Expansion of PIGA and HLA class I mutant HSPCs have been linked to immune evasion from T-cell mediated pressures. We hypothesized that in analogy with antitumor immunity, the pathophysiological cascade of immune escape in IAA is initiated by immunoediting pressures and culminates with mechanisms of clonal evolution characterized by hits in immune recognition and response genes...
January 2023: Leukemia
https://read.qxmd.com/read/36187875/-uba1-screening-in-sweet-syndrome-with-hematological-neoplasms-reveals-a-novel-association-between-vexas-and-chronic-myelomonocytic-leukemia
#32
JOURNAL ARTICLE
Carmelo Gurnari, Peter Mannion, Ishani Pandit, Simona Pagliuca, Maria Teresa Voso, Jaroslaw P Maciejewski, Valeria Visconte, Heesun J Rogers
No abstract text is available yet for this article.
October 2022: HemaSphere
https://read.qxmd.com/read/36157589/a-machine-learning-model-of-response-to-hypomethylating-agents-in-myelodysplastic-syndromes
#33
JOURNAL ARTICLE
Nathan Radakovich, David A Sallman, Rena Buckstein, Andrew Brunner, Amy Dezern, Sudipto Mukerjee, Rami Komrokji, Najla Al-Ali, Jacob Shreve, Yazan Rouphail, Anne Parmentier, Alexandre Mamedov, Mohammed Siddiqui, Yihong Guan, Teodora Kuzmanovic, Metis Hasipek, Babal Jha, Jaroslaw P Maciejewski, Mikkael A Sekeres, Aziz Nazha
Hypomethylating agents (HMA) prolong survival and improve cytopenias in individuals with higher-risk myelodysplastic syndrome (MDS). Only 30-40% of patients, however, respond to HMAs, and responses may not occur for more than 6 months after HMA initiation. We developed a model to more rapidly assess HMA response by analyzing early changes in patients' blood counts. Three institutions' data were used to develop a model that assessed patients' response to therapy 90 days after the initiation using serial blood counts...
October 21, 2022: IScience
https://read.qxmd.com/read/36108594/concomitant-immunosuppressive-therapy-and-eculizumab-use-in-patients-with-paroxysmal-nocturnal-hemoglobinuria-pnh-an-international-pnh-registry-analysis
#34
JOURNAL ARTICLE
Anita Hill, Régis Peffault de Latour, Austin G Kulasekararaj, Morag Griffin, Robert A Brodsky, Jaroslaw P Maciejewski, Jing L- Marantz, Philippe Gustovic, Hubert Schrezenmeier
INTRODUCTION: Complement C5 inhibitor eculizumab is the first approved treatment for paroxysmal nocturnal hemoglobinuria (PNH), a rare hematologic disorder caused by uncontrolled terminal complement activation. Approximately 50% of patients with aplastic anemia (AA) have PNH cells. Limited data are available for patients with AA-PNH taking concomitant immunosuppressive therapy (IST) and eculizumab. METHODS: Data from the International PNH Registry (NCT01374360) were used to evaluate the safety and effectiveness of eculizumab and IST in patients taking IST followed by concomitant eculizumab (IST+c-Ecu) or eculizumab followed by concomitant IST (Ecu+c-IST)...
September 15, 2022: Acta Haematologica
https://read.qxmd.com/read/36077618/multiple-myeloma-therapy-emerging-trends-and-challenges
#35
REVIEW
Danai Dima, Dongxu Jiang, Divya Jyoti Singh, Metis Hasipek, Haikoo S Shah, Fauzia Ullah, Jack Khouri, Jaroslaw P Maciejewski, Babal K Jha
Multiple myeloma (MM) is a complex hematologic malignancy characterized by the uncontrolled proliferation of clonal plasma cells in the bone marrow that secrete large amounts of immunoglobulins and other non-functional proteins. Despite decades of progress and several landmark therapeutic advancements, MM remains incurable in most cases. Standard of care frontline therapies have limited durable efficacy, with the majority of patients eventually relapsing, either early or later. Induced drug resistance via up-modulations of signaling cascades that circumvent the effect of drugs and the emergence of genetically heterogeneous sub-clones are the major causes of the relapsed-refractory state of MM...
August 23, 2022: Cancers
https://read.qxmd.com/read/36054881/clinical-and-molecular-determinants-of-clonal-evolution-in-aplastic-anemia-and-paroxysmal-nocturnal-hemoglobinuria
#36
MULTICENTER STUDY
Carmelo Gurnari, Simona Pagliuca, Pedro Henrique Prata, Jacques-Emmanuel Galimard, Luiz Fernando B Catto, Lise Larcher, Marie Sebert, Vincent Allain, Bhumika J Patel, Arda Durmaz, Andre L Pinto, Mariana C B Inacio, Lucie Hernandez, Nathalie Dhedin, Sophie Caillat-Zucman, Emmanuelle Clappier, Flore Sicre de Fontbrune, Maria Teresa Voso, Valeria Visconte, Régis Peffault de Latour, Jean Soulier, Rodrigo T Calado, Gérard Socié, Jaroslaw P Maciejewski
PURPOSE: Secondary myeloid neoplasms (sMNs) remain the most serious long-term complications in patients with aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH). However, sMNs lack specific predictors, dedicated surveillance measures, and early therapeutic interventions. PATIENTS AND METHODS: We studied a multicenter, retrospective cohort of 1,008 patients (median follow-up 8.6 years) with AA and PNH to assess clinical and molecular determinants of clonal evolution...
January 1, 2023: Journal of Clinical Oncology
https://read.qxmd.com/read/35941213/alternatively-spliced-csf3r-isoforms-in-srsf2-p95h-mutated-myeloid-neoplasms
#37
JOURNAL ARTICLE
Borwyn A Wang, Hrishikesh M Mehta, Srinivasa R Penumutchu, Blanton S Tolbert, Chonghui Cheng, Marek Kimmel, Torsten Haferlach, Jaroslaw P Maciejewski, Seth J Corey
Alternatively spliced colony stimulating factor 3 receptor (CSF3R) isoforms Class III and Class IV are observed in myelodysplastic syndromes (MDS), but their roles in disease remain unclear. We report that the MDS-associated splicing factor SRSF2 affects the expression of Class III and Class IV isoforms and perturbs granulopoiesis. Add-back of the Class IV isoform in Csf3r-null mouse progenitor cells increased granulocyte progenitors with impaired neutrophil differentiation, while add-back of the Class III produced dysmorphic neutrophils in fewer numbers...
August 8, 2022: Leukemia
https://read.qxmd.com/read/35927326/anti-cox-2-autoantibody-is-a-novel-biomarker-of-immune-aplastic-anemia
#38
JOURNAL ARTICLE
Tiina Kelkka, Mikko Tyster, Sofie Lundgren, Xingmin Feng, Cassandra Kerr, Kohei Hosokawa, Jani Huuhtanen, Mikko Keränen, Bhavisha Patel, Toru Kawakami, Yuka Maeda, Otso Nieminen, Tiina Kasanen, Pasi Aronen, Bhagwan Yadav, Hanna Rajala, Hideyuki Nakazawa, Taina Jaatinen, Eva Hellström-Lindberg, Seishi Ogawa, Fumihiro Ishida, Hiroyoshi Nishikawa, Shinji Nakao, Jaroslaw Maciejewski, Neal S Young, Satu Mustjoki
In immune aplastic anemia (IAA), severe pancytopenia results from the immune-mediated destruction of hematopoietic stem cells. Several autoantibodies have been reported, but no clinically applicable autoantibody tests are available for IAA. We screened autoantibodies using a microarray containing >9000 proteins and validated the findings in a large international cohort of IAA patients (n = 405) and controls (n = 815). We identified a novel autoantibody that binds to the C-terminal end of cyclooxygenase 2 (COX-2, aCOX-2 Ab)...
September 2022: Leukemia
https://read.qxmd.com/read/35926182/targeting-the-eif2ak1-signaling-pathway-rescues-red-blood-cell-production-in-sf3b1-mutant-myelodysplastic-syndromes-with-ringed-sideroblasts
#39
JOURNAL ARTICLE
Vera Adema, Feiyang Ma, Rashmi Kanagal-Shamanna, Natthakan Thongon, Guillermo Montalban-Bravo, Hui Yang, Scott A Peslak, Feng Wang, Pamela Acha, Francesc Sole, Pamela Lockyer, Margherita Cassari, Jaroslaw P Maciejewski, Valeria Visconte, Irene Ganan-Gomez, Yuanbin Song, Carlos Bueso-Ramos, Matteo Pellegrini, Tuyet M Tan, Rafael Bejar, Jennifer S Carew, Stephanie Halene, Valeria Santini, Gheath Al-Atrash, Karen Clise-Dwyer, Guillermo Garcia-Manero, Gerd A Blobel, Simona Colla
SF3B1 mutations, which occur in 20% of patients with myelodysplastic syndromes (MDS), are the hallmarks of a specific MDS subtype, MDS with ringed sideroblasts (MDS-RS), which is characterized by the accumulation of erythroid precursors in the bone marrow and primarily affects the elderly population. Here, using single-cell technologies and functional validation studies of primary SF3B1-mutant MDS-RS samples, we show that SF3B1 mutations lead to the activation of the EIF2AK1 pathway in response to heme deficiency and that targeting this pathway rescues aberrant erythroid differentiation and enables the red blood cell maturation of MDS-RS erythroblasts...
August 4, 2022: Blood cancer discovery
https://read.qxmd.com/read/35839275/amplified-epor-jak2-genes-define-a-unique-subtype-of-acute-erythroid-leukemia
#40
JOURNAL ARTICLE
June Takeda, Kenichi Yoshida, Masahiro M Nakagawa, Yasuhito Nannya, Akinori Yoda, Ryunosuke Saiki, Yotaro Ochi, Lanying Zhao, Rurika Okuda, Xingxing Qi, Takuto Mori, Ayana Kon, Kenichi Chiba, Hiroko Tanaka, Yuichi Shiraishi, Ming-Chung Kuo, Cassandra M Kerr, Yasunobu Nagata, Daisuke Morishita, Nobuhiro Hiramoto, Akira Hangaishi, Hideyuki Nakazawa, Ken Ishiyama, Satoru Miyano, Shigeru Chiba, Yasushi Miyazaki, Toshiyuki Kitano, Kensuke Usuki, Nobuo Sezaki, Hisashi Tsurumi, Shuichi Miyawaki, Jaroslaw P Maciejewski, Takayuki Ishikawa, Kazuma Ohyashiki, Arnold Ganser, Michael Heuser, Felicitas Thol, Lee-Yung Shih, Akifumi Takaori-Kondo, Hideki Makishima, Seishi Ogawa
Acute erythroid leukemia (AEL) is a unique subtype of acute myeloid leukemia characterized by prominent erythroid proliferation whose molecular basis is poorly understood. To elucidate the underlying mechanism of erythroid proliferation, we analyzed 121 AEL using whole-genome/exome and/or targeted-capture sequencing, together with transcriptome analysis of 21 AEL samples. Combining publicly available sequencing data, we found a high frequency of gains/amplifications involving EPOR/JAK2 in TP53-mutated cases, particularly those having >80% erythroblasts designated as pure erythroid leukemia (10/13)...
July 15, 2022: Blood cancer discovery
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