e-7107 and Myelodysplastic-Syndromes

The myelodysplastic syndromes (MDS) are common myeloid malignancies showing frequent progression to acute myeloid leukemia (AML). Pre-mRNA splicing is an essential cellular process carried out by the spliceosome. Mutations in splicing factor genes (including SF3B1, SRSF2, U2AF1 and ZRSR2) occur in over half of MDS patients and result in aberrant pre-mRNA splicing of many target genes, implicating aberrant spliceosome function in MDS disease pathogenesis. Recent functional studies have illuminated the impact on hematopoiesis of some aberrantly spliced target genes associated with splicing factor mutations. Emerging data show that the commonly mutated splicing factors have convergent effects on aberrant splicing of mRNAs that promote NF-κB signaling and on R-loop elevation leading to DNA damage, providing novel insights into MDS disease pathophysiology. It is recognized that the survival of splicing factor mutant cells is dependent on the presence of the wildtype allele, providing a rationale for the use of spliceosome inhibitors in splicing factor mutant MDS. Pre-clinical studies involving E7107 and H3B-8800 have shown the potential of these spliceosome inhibitors for the treatment of splicing factor mutant MDS and AML.

Topics: DNA Damage; Epoxy Compounds; Humans; Leukemia, Myeloid, Acute; Macrolides; Mutation; Myelodysplastic Syndromes; Neoplasm Proteins; NF-kappa B; Piperazines; Pyridines; RNA Precursors; RNA Splicing; RNA Splicing Factors; RNA, Neoplasm

Genome sequencing of primary cells from patients with myelodysplastic syndromes (MDS) led to the identification of recurrent heterozygous mutations in gene encoding components of the spliceosome, the cellular machinery which processes pre-messenger RNA (mRNA) to mature mRNA during gene transcription. Splicing mutations are mutually exclusive with one another and collectively represent the most common mutation class in MDS, occurring in approximately 60 % of patients overall and more than 80 % of those with ring sideroblasts. Evidence from animal models suggests that homozygous splicing mutations are lethal, and that in heterozygously mutated models, any further disruption of splicing triggers apoptosis and cell death. MDS cells with spliceosome mutations are thus uniquely vulnerable to therapies targeting splicing, which may be tolerated by healthy cells. The spliceosome is emerging as a novel therapeutic target in MDS and related myeloid neoplasms, with the first clinical trial of a splicing modulator opening in 2016.

Topics: Animals; Epoxy Compounds; Hematologic Neoplasms; Humans; Indoles; Macrolides; Mutation; Myelodysplastic Syndromes; Myeloproliferative Disorders; Ribonucleoprotein, U2 Small Nuclear; RNA Splicing; RNA Splicing Factors; Spliceosomes

Mutations in genes encoding splicing factors (which we refer to as spliceosomal genes) are commonly found in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). These mutations recurrently affect specific amino acid residues, leading to perturbed normal splice site and exon recognition. Spliceosomal gene mutations are always heterozygous and rarely occur together with one another, suggesting that cells may tolerate only a partial deviation from normal splicing activity. To test this hypothesis, we engineered mice to express a mutated allele of serine/arginine-rich splicing factor 2 (Srsf2(P95H))-which commonly occurs in individuals with MDS and AML-in an inducible, hemizygous manner in hematopoietic cells. These mice rapidly succumbed to fatal bone marrow failure, demonstrating that Srsf2-mutated cells depend on the wild-type Srsf2 allele for survival. In the context of leukemia, treatment with the spliceosome inhibitor E7107 (refs. 7,8) resulted in substantial reductions in leukemic burden, specifically in isogenic mouse leukemias and patient-derived xenograft AMLs carrying spliceosomal mutations. Whereas E7107 treatment of mice resulted in widespread intron retention and cassette exon skipping in leukemic cells regardless of Srsf2 genotype, the magnitude of splicing inhibition following E7107 treatment was greater in Srsf2-mutated than in Srsf2-wild-type leukemia, consistent with the differential effect of E7107 on survival. Collectively, these data provide genetic and pharmacologic evidence that leukemias with spliceosomal gene mutations are preferentially susceptible to additional splicing perturbations in vivo as compared to leukemias without such mutations. Modulation of spliceosome function may thus provide a new therapeutic avenue in genetically defined subsets of individuals with MDS or AML.

Topics: Anemia, Aplastic; Animals; Bone Marrow Diseases; Bone Marrow Failure Disorders; Bone Marrow Transplantation; Catalysis; Cell Line, Tumor; Epoxy Compounds; Flow Cytometry; Gene Knock-In Techniques; Hemizygote; Hemoglobinuria, Paroxysmal; Humans; Leukemia, Myeloid, Acute; Macrolides; Mice; Mice, Knockout; Mutation; Myelodysplastic Syndromes; Neoplasm Transplantation; Reverse Transcriptase Polymerase Chain Reaction; RNA Splicing; Serine-Arginine Splicing Factors; Spliceosomes