Minor intron retention drives clonal hematopoietic disorders and diverse cancer predisposition

Daichi Inoue, Jacob T. Polaski, Justin Taylor, Pau Castel, Sisi Chen, Susumu Kobayashi, Simon J. Hogg, Yasutaka Hayashi, Jose Mario Bello Pineda, Ettaib El Marabti, Caroline Erickson, Katherine Knorr, Miki Fukumoto, Hiromi Yamazaki, Atsushi Tanaka, Chie Fukui, Sydney X. Lu, Benjamin H. Durham, Bo Liu, Eric WangSanjoy Mehta, Daniel Zakheim, Ralph Garippa, Alex Penson, Guo Liang Chew, Frank McCormick, Robert K. Bradley, Omar Abdel-Wahab

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Most eukaryotes harbor two distinct pre-mRNA splicing machineries: the major spliceosome, which removes >99% of introns, and the minor spliceosome, which removes rare, evolutionarily conserved introns. Although hypothesized to serve important regulatory functions, physiologic roles of the minor spliceosome are not well understood. For example, the minor spliceosome component ZRSR2 is subject to recurrent, leukemia-associated mutations, yet functional connections among minor introns, hematopoiesis and cancers are unclear. Here, we identify that impaired minor intron excision via ZRSR2 loss enhances hematopoietic stem cell self-renewal. CRISPR screens mimicking nonsense-mediated decay of minor intron-containing mRNA species converged on LZTR1, a regulator of RAS-related GTPases. LZTR1 minor intron retention was also discovered in the RASopathy Noonan syndrome, due to intronic mutations disrupting splicing and diverse solid tumors. These data uncover minor intron recognition as a regulator of hematopoiesis, noncoding mutations within minor introns as potential cancer drivers and links among ZRSR2 mutations, LZTR1 regulation and leukemias.

Original languageEnglish (US)
Pages (from-to)707-718
Number of pages12
JournalNature genetics
Volume53
Issue number5
DOIs
StatePublished - May 2021

ASJC Scopus subject areas

  • Genetics

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