2. Academic Validation
  3. METTL3-Mediated m6A Modification Controls Splicing Factor Abundance and Contributes to Aggressive CLL

METTL3-Mediated m6A Modification Controls Splicing Factor Abundance and Contributes to Aggressive CLL

  • Blood Cancer Discov. 2023 Apr 17;OF1-OF18. doi: 10.1158/2643-3230.BCD-22-0156.
Yiming Wu # 1,  Meiling Jin # 1,  Mike Fernandez 1,  Kevyn L Hart 1,  Aijun Liao 1,  Xinzhou Ge 2 3,  Stacey M Fernandes 4,  Tinisha McDonald 5 6,  Zhenhua Chen 1,  Daniel Röth 7,  Lucy Y Ghoda 5 6,  Guido Marcucci 5 6 8,  Markus Kalkum 7,  Raju K Pillai 9,  Alexey V Danilov 8 10,  Jingyi Jessica Li 2 3,  Jianjun Chen 1,  Jennifer R Brown 4,  Steven T Rosen 8 10,  Tanya Siddiqi 8 10,  Lili Wang 1 10
Affiliations

Affiliations

  • 1 Department of Systems Biology, Beckman Research Institute, City of Hope National Comprehensive Cancer Center, Monrovia, California.
  • 2 Department of Statistics, University of California, Los Angeles, California.
  • 3 Department of Computational Medicine, University of California, Los Angeles, California.
  • 4 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 5 The Hematopoietic Tissue Biorepository, City of Hope National Comprehensive Cancer Center, Duarte, California.
  • 6 Department of Hematological Malignancies Translational Sciences, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California.
  • 7 Department of Molecular Imaging and Therapy, Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, California.
  • 8 Department of Hematology & Hemato-poietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, California.
  • 9 Department of Pathology, City of Hope National Comprehensive Cancer Center, Duarte, California.
  • 10 Toni Stephenson Lymphoma Center, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California.
  • # Contributed equally.
PMID: 37067905 DOI: 10.1158/2643-3230.BCD-22-0156
Abstract

RNA splicing dysregulation underlies the onset and progression of cancers. In chronic lymphocytic leukemia (CLL), spliceosome mutations leading to aberrant splicing occur in ∼20% of patients. However, the mechanism for splicing defects in spliceosome-unmutated CLL cases remains elusive. Through an integrative transcriptomic and proteomic analysis, we discover that proteins involved in RNA splicing are posttranscriptionally upregulated in CLL cells, resulting in splicing dysregulation. The abundance of splicing complexes is an independent risk factor for poor prognosis. Moreover, increased splicing factor expression is highly correlated with the abundance of METTL3, an RNA methyltransferase that deposits N6-methyladenosine (m6A) on mRNA. METTL3 is essential for cell growth in vitro and in vivo and controls splicing factor protein expression in a methyltransferase-dependent manner through m6A modification-mediated ribosome recycling and decoding. Our results uncover METTL3-mediated m6A modification as a novel regulatory axis in driving splicing dysregulation and contributing to aggressive CLL.

Significance: METTL3 controls widespread splicing factor abundance via translational control of m6A-modified mRNA, contributes to RNA splicing dysregulation and disease progression in CLL, and serves as a potential therapeutic target in aggressive CLL. See related commentary by Janin and Esteller.

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