t(8;9) (p22;p24) and i(17q) in therapy related myeloid neoplasms

Background
Therapy-related myeloid neoplasms (t-MN) are clonal hematopoietic stem cell disorders arising as a late complication following radiation and/or cytotoxic therapy (chemotherapy with alkylating agents or topoisomerase II inhibitors) administered for a primary malignant condition, organ transplant or autoimmune diseases1. The term ‘therapy-related’ leukemia is descriptive and is based on a patient’s history of exposure to cytotoxic agents. So, t-MNs are realized and categorized according to the primary treatment and the corresponding genetic and molecular lesions2. Translocations involving the JAK2 locus have an oncogenic significance in hematological malignancies. One of these translocation is t(8;9) (p22;p24) which results in human autoantigen pericentriolar material gene 1-Janus activated kinase 2 gene (PCM1-JAK2) fusion gene3. Also, Isochromosome 17q is a cytogenetic abnormalities detected in several hematological disorders. It leads to characteristic morphologic features such as pseudo-Pelger-Huet neutrophils and small hypolobated megakaryocytes4.We aimed in this study to detect the frequency of t(8;9) (p22;p24) and i(17q) by fluorescent in situ hybridization in the two sub-types of therapy related myeloid neoplasms (t-MDS/t-AML) and also determine the association of t(8;9) and i(17q) with type of therapy, time of exposure and prognostic criteria.


Patients and methods
A cross–sectional analytic study included 73 t-MN patients and 66 patients with newly diagnosed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), who were tested for t(8;9) and i(17q) by fluorescent in situ hybridization technique. At least 200 metaphases were analyzed for each patient.


Results
Translocation (8;9) and i(17q) were detected only in cases of t-MDS (15.8 and 7.0%, respectively) and de novo AML cases (5.9 and 15.7%, respectively) with no significant difference between the four studied groups t-MDS, t-AML, de novo AML and MDS. Primary malignancies in t(8;9) positive t-MDS patients were Ewing’s sarcoma, non-hodjkin lymphoma (NHL), AML M4 and T ALL which is the most frequent one. While primary malignancy in i(17q) positive t-MDS was T-acute lymphoblastic leukemia (T-ALL). Alkylating agents and plant alkaloids were the only implicated therapy in patients with t-MN and positive either for t(8;9) or i(17q). Concerning latency period, there is a significant difference between positive and negative cases of t(8;9) (P<0.001) with being shorter latency in positive cases (median 5 months). However, during comparing the latency period between positive and negative cases of i(17q), there is no significant difference between two groups (P<0.697) with being shorter latency in negative cases (median 5 months).


Conclusion
In conclusion, to the best of our knowledge, the present study is the first to report the frequency of t(8;9) and i(17q) in a relatively large number of t-MN cases. Both t(8;9) (p22;p24) and i 17q are uncommon mutations in t-MN and had been detected only in cases of t-MDS and these cases were associated with heterogenous clinical course. However, the detection of PCM1-JAK2 fusion gene in t-MN cases has clinical importance as there may be some response to tyrosine kinase inhibitors. Further studies are recommended to ensure either that t(8;9) (p22;p24) and i 17q are parts of oncogenic events that precede the primary malignancy or sequels of primary malignancy pathogenesis and/or therapy leads to t- MN.