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1 May 2023
Cover ImageNonmutational epigenetic reprogramming has emerged as a hallmark of cancer, responsible for the acquisition of oncogenic gene-expression programs independent of genetic mutations. Among such epigenetic mechanisms is posttranscriptional modulation of gene expression, by which particular transcripts undergo differential splicing, chemical modification, or other processes that affect downstream protein abundance. On p. 180, Vujovic, de Rooij et al. screen RNA-binding genes for their essentiality in acute myeloid leukemia (AML) stem cells (LSC), identifying ELAVL1 as a protein factor that promotes LSC-associated metabolic and differentiation patterns via altered splicing and transcript stabilization. Wu, Jin, et al., on p. 228 and In The Spotlight by Janin and Esteller on p. 176, observe that METTL3-mediated m6A modification of splicing factor transcripts leads to increased translation efficiency and subsequent global splicing dysregulation as a driver of chronic lymphocytic leukemia (CLL) in which no splicing mutations have occurred. Both studies highlight the targeting of key RNA-binding proteins as potential therapeutic vulnerabilities in hematologic malignancies. The cover illustration represents an abstract view of RNA-protein interactions, increasingly found to be a central regulatory step in oncogenesis. Cover image by Tetiana Vavryk.Close Modal
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In This Issue
In the Spotlight
Defective Immunity Against SARS-CoV-2 Omicron Variants Despite Full Vaccination in Hematologic Malignancies
Global Shift in Alternative Splicing and Therapeutic Susceptibilities in Leukemia Driven by METTL3 Overexpression
In Vivo Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Ana Vujovic; Laura de Rooij; Ava Keyvani Chahi; He Tian Chen; Brian A. Yee; Sampath K. Loganathan; Lina Liu; Derek C.H. Chan; Amanda Tajik; Emily Tsao; Steven Moreira; Pratik Joshi; Joshua Xu; Nicholas Wong; Zaldy Balde; Soheil Jahangiri; Sasan Zandi; Stefan Aigner; John E. Dick; Mark D. Minden; Daniel Schramek; Gene W. Yeo; Kristin J. Hope
Diverse RNA-binding protein dependencies are identified for AML leukemic stem cells (LSC). Inhibition of ELAVL1 impairs splicing and RNA stabilization that supports LSC mitochondrial metabolism, identifying a novel therapeutic vulnerability.
Molecular Evolution of Classic Hodgkin Lymphoma Revealed Through Whole-Genome Sequencing of Hodgkin and Reed Sternberg Cells
Francesco Maura; Bachisio Ziccheddu; Jenny Z. Xiang; Bhavneet Bhinder; Joel Rosiene; Federico Abascal; Kylee H. Maclachlan; Kenneth Wha Eng; Manik Uppal; Feng He; Wei Zhang; Qi Gao; Venkata D. Yellapantula; Vicenta Trujillo-Alonso; Sunita I. Park; Matthew J. Oberley; Elizabeth Ruckdeschel; Megan S. Lim; Gerald B. Wertheim; Matthew J. Barth; Terzah M. Horton; Andriy Derkach; Alexandra E. Kovach; Christopher J. Forlenza; Yanming Zhang; Ola Landgren; Craig H. Moskowitz; Ethel Cesarman; Marcin Imielinski; Olivier Elemento; Mikhail Roshal; Lisa Giulino-Roth
Whole-genome sequencing of Hodgkin lymphoma identifies driver events and reconstructs their acquisition timing during B-cell ontogenesis and oncogenesis.
METTL3-Mediated m6A Modification Controls Splicing Factor Abundance and Contributes to Aggressive CLL
Yiming Wu; Meiling Jin; Mike Fernandez; Kevyn L. Hart; Aijun Liao; Xinzhou Ge; Stacey M. Fernandes; Tinisha McDonald; Zhenhua Chen; Daniel Röth; Lucy Y. Ghoda; Guido Marcucci; Markus Kalkum; Raju K. Pillai; Alexey V. Danilov; Jingyi Jessica Li; Jianjun Chen; Jennifer R. Brown; Steven T. Rosen; Tanya Siddiqi; Lili Wang
METTL3 regulates RNA splicing dysregulation to contribute to aggressive CLL via m6A modification-dependent translational control of splicing factors.
Expression of Concern
Expression of Concern: Clonal Hematopoiesis Is Associated with Increased Risk of Severe Neurotoxicity in Axicabtagene Ciloleucel Therapy of Large B-Cell Lymphoma