NOTCH1 and SF3B1
mutations can be added to the hierarchical prognostic classification in chronic lymphocytic leukemia.
Among AML with myelodysplasia-related changes (AML-MRC) and therapy-related AML (t-AML), mutations in splicing factors genes such as SRSF2, SF3B1
, U2AF1, ZRSR2, mutations on chromatin/histone modifications like ASXL1, EZH2, BCOR, STAG2, and TP53 mutations are common (53).
Here, we screened epigenetic modulators associated with different complexes and core splicing factors by shRNA mediated loss of function assays and identified splicing factors Sf3a1 and Sf3b1
that are required for direct cardiac reprogramming.
mutations in chronic lymphocytic leukemia," Blood, vol.
Genes Prognostic Impact Epigenetic Regulators TET2 poor Ezra poor ASXL1 poor DNMT3A poor IDH1/IDH2 poor Spliceosomal genes SF3B1
good U2AF1 poor SRSF2 poor ZRSR2 unknown Cytoplasmic tyrosine kinases JAK2 poor Signaling molecules SETBP1 poor NRAS poor Transcriptional factors ETV6 poor RUNX1 poor Tumor suppressors TP53 poor ROBO1/ROBO2 poor Chromatid cohesion STAG2 poor Table 2: Ongoing and future monotherapy and combination phase I/II trials with immune checkpoint inhibitors in MDS and interim results.
With this in mind, we have developed ddPCR assays to detect mutations in the splicing factor 3B subunit 1 (SF3B1
)  gene for future use as a biomarker of response to novel targeted therapies (7-10).
Class I signaling FLT3 JAK2 MPL NF1 CBL LNK CBLB PTP11 Class II transcription factors CEBPA ETV6 NPM1 RARA RUNX1 Class III epigenetic regulators DNMT3A IDH1 IDH2 TET2 ASXL1 EZH2 PHF6 UTX EED Class IV tumor suppressor genes TP53 WT1 CDKN2A CDKN2B Class V RNA maturation SF3B1
SRSF2 U2AF1 SF1 SF3A1 PRPF40B One frequently mutated epigenetic regulator in AML is DNMT3A, with approximately 22% of CN-AML patients carrying a DNMT3A mutation .
In one study, SF3B1
, located on chromosome 2 (http://genome.ucsc.edu) was found to be mutated in 20% of all MDS cases and 65% of those with ring sideroblasts .
The company has worldwide rights to worldwide rights to nucleophosmin-1 (NPM1), an informative biomarker for acute myelogenous leukemia (AML) and mutations in the SF3B1
In contrast to the previously described mutations, splicing factor 3b subunit 1 (SF3B1
) gene mutations have been found at a rate of 19% in uveal melanomas and are associated with good prognosis.
(56) Moreover, among splicesome mutations, SF3B1
mutations are closely associated with a specific type of MDS, RARS (refractory anemia with ringed sideroblast); 57-75% of RARS patients harbor SF3B1