Therapy Related Myelodysplastic Syndrome and Therapy Related Acute Myeloid Leukemia Clinical Trial
Official title:
SRSF2 Gene Mutation in Patients With Therapy Related Myelodysplastic Syndromes / Acute Myeloid Leukemia
- To detect SRSF2 gene mutation by polymerase chain reaction (PCR) in the two types of
t-MDS/AML which recognized in the WHO classification.
- Association between SRSF2 gene mutation and the presence of other cytogenetic
abnormalities in the two types of t-MDS/AML which recognized in the WHO classification,
e.g. (Loss of chromosome 7 or del(7q), del(5q), isochromosome 17q, recurrent balanced
chromosomal translocations involving chromosomal segments 11q23 (KMT2A, previously
called MLL) or 21q22.1 (RUNX1), and PML-RARA).
- Relationship between SRSF2 gene mutation and cumulative dose, dose intensity, time of
exposure and prognostic criteria (disease free survival, overall survival and disease
course).
Therapy-related myeloid neoplasms (t-MNs) are a group of hematologic diseases that arise
after chemotherapy and/or radiation therapy for a previous cancer or rarely autoimmune
diseases.
The revised 2016 World Heath Organization (WHO) classification defines t-MN as a subgroup of
acute myeloid leukemia (AML) comprising myelodysplastic syndrome (t-MDS), acute myeloid
leukemia (t-AML), and myelodysplastic/myeloproliferative neoplasms (t-MDS/MPN) .
Two forms of t-MN have been recognized. Alkylating agent/radiation-related t-MN usually
appears 4 to 7 years, which is frequently associated with unbalanced chromosomal
abnormalities involving chromosomes 5 and/or 7, as well mutations or loss of TP53 ( tumor
protein 53).
In contrast, a combination of different topoisomerase II inhibitor-related t-MNs is
associated with a high incidence of recurrent balanced translocations involving chromosomal
segments 11q23 (KMT2A), 21q22 (RUNX1), and PML-RARA [1].
T-MNs are characterized by a subset of molecular mutations including SRSF2, SF3B1, U2AF1,
ZRSR2, ASXL1, STAG2, and TP53.
RNA splicing is a process that produces mature mRNAs by excising introns and splicing exons
from pre-messenger RNA. The spliceosome mutations induce an abnormally spliced mRNA species
and compromising hematopoiesis.
One of the potential candidate genes involved in the RNA splicing pathway is serine and
arginine rich splicing factor 2 (SRSF2). SRSF2, located on chromosome 17q25.1, and plays a
role in preventing exon skipping, confirming the accuracy of splicing and regulating
alternative pre-mRNA splicing. Many studies have already reported the potential prognostic
value of SRSF2 mutations, which have an adverse prognostic impact on survival and disease
progression.
Somatic mutations recently identified in patients with de novo AML and MDS, such as those of
epigenetic regulators, spliceosome machinery and SETBP1, are rare, with the exception of
SRSF2.
TP53 mutations have been associated to the occurrence of cytogenetic abnormalities and poor
response to chemotherapy that are typical of t-MN.
On the other hand, several studies have shown that the presence of isochromosome 17q i(17q)
abnormality is associated with wild-type TP53 and mutations in SETBP1 and SRSF2.
Also, somatic loss of one copy of the long arm of chromosome 7 del(7q) is associated with
unfavorable prognosis and can co-occur with the SRSF2 mutation in patients with MDS and AML.
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