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BLOOD COMMENTARIES

PLENARY PAPER

Up to 30% of patients with trisomy 21 develop transient abnormal myelopoiesis (TAM), and many progress to acute megakaryoblastic leukemia (AMKL), both in association with mutations in the GATA-1 transcription factor. In a Plenary Paper, Alejo-Valle et al demonstrate that miR-125b on chromosome 21 synergizes with mutant GATA-1 to promote leukemogenesis through the repression of ARID3A. Restoring ARID3A expression restores megakaryocytic differentiation and blocks the expansion of GATA-1mutant stem cells.

REVIEW ARTICLE

Eyre et al review the current state of the art of the treatment of mantle cell lymphoma that relapses after immunochemotherapy and autologous stem cell transplantation. They discuss Bruton tyrosine kinase (BTK) inhibitors and the mechanisms of BTK inhibitor resistance, chimeric antigen receptor T-cell therapy, and subsequent novel therapies.

CLINICAL TRIALS AND OBSERVATIONS

Herishanu and colleagues evaluated the efficacy of a third dose of COVID-19 vaccine in 172 patients with chronic lymphocytic leukemia (CLL) who were seronegative after 2 previous doses. Seropositivity was achieved in 25%, with 40% of off-therapy or therapy-naïve patients but only 12% of patients on anti-B-cell therapy responding. This study supports repeated vaccine dosing in this high-risk population but also underscores the need for continued careful protective practices and availability of antibody treatment in nonresponders.

Richter syndrome responds poorly to chemotherapy and has a median survival of 3 to 6 months. Davids et al report results of a phase 2 trial of venetoclax plus chemoimmunotherapy in 26 patients. Complete response was achieved in 50% of patients, with a median overall survival of 19.6 months.

HEMATOPOIESIS AND STEM CELLS

IMMUNOBIOLOGY AND IMMUNOTHERAPY

LYMPHOID NEOPLASIA

Anaplastic large cell lymphoma (ALCL) frequently carries anaplastic lymphoma kinase (ALK) gene fusions, and tyrosine kinase inhibitors (TKIs) can treat ALCL that relapses after chemotherapy. However, TKIs are not curative and relapses occur. Using a genomic loss-of-function screen, Atabay et al found that resistance is driven by PTPN1 and PTPN2 through binding and phosphorylation of ALK and the ALK signaling mediator SHP2, leading to hyperactivity of SHP2, MAPK, and JAK/STAT signaling. Blockade of SHP2 increases sensitivity of ALCL to the ALK inhibitor crizotinib.

Ferdinando Bonfiglio,Alessio Bruscaggin,Francesca Guidetti,Lodovico Terzi di Bergamo,Martin Faderl,Valeria Spina,Adalgisa Condoluci,Luisella Bonomini,Gabriela Forestieri,Ricardo Koch,Deborah Piffaretti,Katia Pini,Maria Cristina Pirosa,Micol Giulia Cittone,Alberto Arribas,Marco Lucioni,Guido Ghilardi,Wei Wu,Luca Arcaini,Maria Joao Baptista,Gabriela Bastidas,Silvia Bea,Renzo Boldorini,Alessandro Broccoli,Marco Matteo Buehler,Vincenzo Canzonieri,Luciano Cascione,Luca Ceriani,Sergio Cogliatti,Paolo Corradini,Enrico Derenzini,Liliana Devizzi,Sascha Dietrich,Angela Rita Elia,Fabio Facchetti,Gianluca Gaidano,Juan Fernando Garcia,Bernhard Gerber,Paolo Ghia,Maria Gomes da Silva,Giuseppe Gritti,Anna Guidetti,Felicitas Hitz,Giorgio Inghirami,Marco Ladetto,Armando Lopez-Guillermo,Elisa Lucchini,Antonino Maiorana,Roberto Marasca,Estella Matutes,Veronique Meignin,Michele Merli,Alden Moccia,Manuela Mollejo,Carlos Montalban,Urban Novak,David Graham Oscier,Francesco Passamonti,Francesco Piazza,Stefano Pizzolitto,Alessandro Rambaldi,Elena Sabattini,Gilles Salles,Elisa Santambrogio,Lydia Scarfò,Anastasios Stathis,Georg Stüssi,Julia T. Geyer,Gustavo Tapia,Corrado Tarella,Catherine Thieblemont,Thomas Tousseyn,Alessandra Tucci,Giorgio Vanini,Carlo Visco,Umberto Vitolo,Renata Walewska,Francesco Zaja,Thorsten Zenz,Pier Luigi Zinzani,Hossein Khiabanian,Arianna Calcinotto,Francesco Bertoni,Govind Bhagat,Elias Campo,Laurence De Leval,Stefan Dirnhofer,Stefano A. Pileri,Miguel A. Piris,Alexandra Traverse-Glehen,Alexander Tzankov,Marco Paulli,Maurilio Ponzoni,Luca Mazzucchelli,Franco Cavalli,Emanuele Zucca,Davide Rossi

Splenic marginal zone lymphoma (SMZL) is a heterogeneous disorder with variable clinical outcomes. Bonfiglio et al report on a genetic and phenotypic analysis of SMZL, defining 2 major and 2 minor genetic clusters with divergent gene expression signatures and clinical outcomes. They also characterize 2 micro environmental phenotypes based on immune cell infiltration, one immune suppressive and the other immune excluded. This new classification provides insights for future targeted therapies.

MYELOID NEOPLASIA

Although chronic myeloid leukemia (CML) in chronic phase responds to tyrosine kinase inhibitors (TKIs), leukemia stem cells persist and provide a source for relapse upon discontinuation of TKIs. Zhao et al performed a meta-analysis of published CML transcriptomes, identifying low expression of MS4A3 as a prominent feature in TKI-resistant stem cells and blasts. They demonstrate that MS4A3 promotes differentiation by increasing cytokine receptor expression, suggesting that overexpression of MS4A3 should overcome TKI resistance.

PHAGOCYTES, GRANULOCYTES, AND MYELOPOIESIS

Severe congenital neutropenia (SCN) is a rare congenital disorder associated with agranulocytosis that has been linked to mutations in several different genes. Warren and colleagues report that heterozygous missense mutations in caseinolytic peptidase B (CLPB) are a novel cause of SCN. Unlike the pathophysiology of most forms of SCN, this mutation does not cause activation of the unfolded protein response and intramedullary apoptosis but causes apoptosis related to mitochondrial dysfunction.

LETTER TO BLOOD

BLOOD WORK

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