الفهرس 
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Abstract
Therapy-related myeloid neoplasms constitute a group of disorders occurring because of iatrogenic somatic mutations induced by cytotoxic chemotherapy or radiotherapy. The 2016 WHO classification categorizes t-MNs into subtypes based on the causative agents, such as alkylating agents/radiotherapy or topoisomerase II inhibitors. Additionally, other therapies causally associated with t-MNs include antimetabolites, anthracyclines, antimicrotubule (antitubulin) agents often used in combination with other cytotoxic agents, and ionizing radiation.
The advancement in therapeutic strategies for treating hematologic and solid tumors has resulted in longer life expectancy for patients. The latency period between exposure to anticancer drugs and the development of t-MNs can range from several months to up to 10 years. Several factors influence this latency period, including the age at diagnosis of the primary malignancy, the type of malignancy, the cytotoxic treatment regimen administered previously, the cumulative dose and intensity of treatment received.
Proposed models for t-MNs development include direct oncogene induction, induction of genetic instability enabling complex aberrations, selection of treatment-resistant clones, and inherited cancer susceptibility contributing to multiple malignancies in patients.
Mutations in genes encoding splicing factors are common mutations found in different cancer types. RNA splicing is a tightly regulated process essential for producing mature mRNA molecules by removing introns and joining exons from pre-mRNA. However, mutations in spliceosome genes disrupt the recognition of 3’-splice site during pre-mRNA processing. This disruption leads to the production of abnormally spliced mRNA species, ultimately compromising hematopoiesis and contributing to the development of cancer.
Recurrent somatic mutations in genes encoding core spliceosomal proteins, such as SF3B1, SRSF2, U2AF1, and ZRSR2, have been discovered in diverse cancer types, including hematological malignancies like MDS, CLL, and in solid tumors. Spliceosomal gene mutations are mutually exclusive and may indicate either proto-oncogenic or tumor suppressor roles, depending on the specific gene affected.
The SRSF2 gene, located on chromosome 17q25.2, encodes a member of the SR protein family involved in pre-mRNA splicing. Mutations in SRSF2, particularly at residue proline 95, are recurrent in various hematological malignancies. These mutations correlate with poor prognosis, suggesting functional differences compared to other spliceosomal mutations.
Aim of the work:
1. To detect SRSF2 gene mutation status in in the two types of t-MDS/AML which recognized in the WHO classification.
2. Relation 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), lsochromosome 17q, recurrent balanced chromosomal translocations involving chromosomal segments 11q23 (KMT2A, previously called MLL) or 21q22.1 (RUNX1), and PML-RARA).
3. Relation between SRSF2 gene mutation and cumulative dose, dose intensity, time of exposure and prognostic criteria (disease free survival, overall survival and disease course).
The current study involved 47 patients with t-MNs (35 t-MDS and 12 t-AML) who developed MNs after therapy to primary malignancies (hematological and non-hematological malignancies) and 44 patients with de novo MNs (19 MDS and 25 AML). All cases were collected from Clinical Hematology Department at Assiut University Hospital and the South Egypt Cancer Institute from 2019 to 2022.