Minor intron retention drives clonal hematopoietic disorders and diverse cancer predisposition

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 1 – 4 . Although hypothesized to serve important regulatory functions 5 , physiologic roles for the minor spliceosome are not well understood. For example, the minor spliceosome component ZRSR2 is subject to recurrent, leukemia-associated mutations 6 – 9 , yet functional connections between 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 mRNAs converged on LZTR1, a regulator of Ras-related GTPases 10 – 12 . 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 between ZRSR2 mutations, LZTR1 regulation, and leukemias.

Transcription Factors, R-Loops and Deubiquitinating Enzymes: Emerging Targets in Myelodysplastic Syndromes and Acute Myeloid Leukemia

“…In this model, Zrsr2 loss leads to a global impairment of U12-type intron splicing with over one-third of U12-type introns exhibiting significantly increased retention. Interestingly, Zrsr2-null HSCs show enhanced self-renewal and MDS [183].…”

“…Very recently, to investigate the impact of ZRSR2 mutations on minor intron splicing, Inoue and colleagues created a mouse model through the conditional Cre-mediated excision of exon 4 of Zrsr2, resulting in an early frameshift [183]. In this model, Zrsr2 loss leads to a global impairment of U12-type intron splicing with over one-third of U12-type introns exhibiting significantly increased retention.…”

Mechanistic Insights of Aberrant Splicing with Splicing Factor Mutations Found in Myelodysplastic Syndromes

“…Most recently, it was demonstrated that impaired minor intron excision by knock-out of ZRSR2 protein enhances hematopoietic stem cell self-renewal, and mutations in minor introns are suggested to be potential cancer drivers [83]. However, the precise molecular mechanism how ZRSR2 mutations affect minor intron splicing remains to be elucidated.…”

Minor Intron Splicing from Basic Science to Disease

“…The congenital disorders related to minor intron splicing include: spondyloepiphyseal dysplasia tarda (SEDT) [ 86 ], Microcephalic Osteodysplastic Primordial Dwarfism type I/III or Taybi-Linder syndrome (MOPDI/III or TALS) [ 89 , 104 ], Roifman syndrome (RFMN) [ 91 ], Lowry Wood syndrome (LWS) [ 90 ], early-onset cerebellar ataxia (EOCA) [ 87 ], isolated growth hormone deficiency (IGHD) [ 74 ] (reviewed in [39.72]), and Noonan syndrome [ 88 ]. On the other hand, the neurodegenerative diseases include spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) (reviewed in [ 39 , 72 ]).…”

“…However, the high similarity of the two pathways in their physiological states and the prevalence of alternative splicing in the minor splicing pathway [ 55 ] suggest that the two pathways are affected similarly in pathological states. Furthermore, the minor splicing system has been linked to myelodysplastic syndrome [ 71 , 88 ] and Peutz-Jegher’s syndrome [ 85 ], which increase the risk of acute myeloid leukemia [ 71 ] and gastrointestinal/extra gastrointestinal cancers [ 105 ], respectively. The cause of six congenital diseases and two neurodegenerative disorders have been attributed completely or in part to the minor splicing pathway.…”