Editors' ChoiceCancer

TERT, cancer, scissors

See allHide authors and affiliations

Science Translational Medicine  03 Jun 2015:
Vol. 7, Issue 290, pp. 290ec92
DOI: 10.1126/scitranslmed.aac5090

Chromosome-capping telomere sequences shorten with each DNA replication cycle. Excessive telomere attrition due to aging or inactivation of telomerase causes genetic damage, myelodysplastic syndrome (MDS), and cancer. Inexplicably, cancers often contain mutations affecting the spliceosome, a molecular machine that regulates splicing of nascent mRNAs. Recently published work revealed a therapeutically relevant signaling network that connects telomere shortening to faulty mRNA maturation, MDS, and cancer.

Colla et al. discovered that mice deficient in Tert (the catalytic telomerase subunit) develop MDS and leukemia after a few generations of telomerase-free breeding. Of note, the net timing of symptoms roughly recapitulates the onset of clinical issues in children with inherited telomerase disorders. Surprisingly, telomerase reactivation rescued some of these abnormalities in vivo, indicating that bone marrow with short telomeres can be successfully repaired. How do short telomeres hamper this repair process? According to Colla et al., telomere erosion impairs splicing of a collection of genes essential for spliceosome activity, DNA repair, and mitotic chromosome segregation. These genes represent potential therapeutic targets in MDS, leukemia, and inherited bone marrow failure syndromes resulting from telomere attrition.

This signaling circuit may be exploited therapeutically with more precision if spliceosome mutations impose the malignant behavior on stem cells through selective disruption of downstream pathways. Indeed, this may be the case. Shirai et al. generated MDS-prone transgenic mice that express the disease-associated mutant U2af1S34F spliceosome subunit. The UAF1S34F mutation impaired the spliceosome’s ability to recognize a defined splicing site, causing erroneous maturation of multiple transcripts associated with MDS and leukemia. Similarly, Kim et al. showed that mice expressing another MDS-linked spliceosome mutation, Srsf2P95H, recapitulate myelodysplasia and hematopoietic stem cell dysfunction seen in SRSFP95H patients. Comprehensive evaluation of RNA splicing abnormalities in SRSFP95H humans and mice identified a large set of disease-relevant transcripts affected by the SRSFP95H mutation, including another key MDS-associated gene, EZH2.

Together, erosion of telomeres and spliceosome malfunction unleash a self-perpetuating cascade of impaired gene expression, culminating in genome instability, bone marrow failure, and cancer. Future research will determine if this vicious cycle can be broken with a precision therapeutic attack against the signaling pathways identified in this work and follow-up studies.

S. Colla et al., Telomere dysfunction drives aberrant hematopoietic differentiation and myelodysplastic syndrome. Cancer Cell 27, 644–657 (2015). [Abstract]

C. L. Shirai et al., Mutant U2AF1 expression alters hematopoiesis and pre-mRNA splicing in vivo. Cancer Cell 27, 631–643 (2015). [Abstract]

E. Kim et al., SRSF2 mutations contribute to myelodysplasia by mutant-specific effects on exon recognition. Cancer Cell 27, 617–630 (2015). [Abstract]

Stay Connected to Science Translational Medicine

Navigate This Article