Can Activation Induced Cytidine Deaminase Lead to Genetic Instability in Bcr-Abl Negative Myeloproliferative Neoplasms?
Authors: Dermenci Hasan , Daglar Aynur , Akadam Basak Peker , Hancer Veysel Sabri , Gelmez Yusuf , Aktan Melih , Nalcaci Meliha , Yavuz Akif S. 
Published: October 2019

Abstract 5056

Objective:

Most patients with myeloproliferative neoplasms (MPN) have mutations that lead to constitutive activation of the tyrosine kinase signal transduction pathways. JAK2V617F mutation is present in about 97% of polycythemia vera (PV), and in 60% of essential thrombocythemia (ET) and primary myelofibrosis (PMF) patients. JAK2-exon-12 mutations, MPL exon-10-mutations are also seen in MPNs. In addition to this mutations, some patients with MPN may acquire mutations of other genes, such as in genes involved in negative regulations of signaling pathways (LNK, CBL, SOCS1, SOCS2, SOCS3) and epigenetic regulations (TET2, ASXL1, DNMT3A, or EZH2). IKZF1 deletions and TP53 mutations are mainly found post-MPN acute myeloid leukemia (AML). Loss of function mutations in TET2, ASXL1 and EZH2 genes, may be early events preceding JAK2V617F but may also secondary genetic event. These mutations are more frequently observed in PMF than in PV and ET. They are also present in other myeloid malignancies such as myelodysplasia and AML. Moreover several cases have been described that are positive for BCR-ABL and JAK2V617F mutation. It is thought that the mutagenic phenotype existing inherently in patients with MPN can generate new mutations. With the contribution of these mutations, PV, ET and PMF might evolve into secondary myelofibrosis or leukemia at different ratios. Activation induced cytidine deaminase (AID) is required for a B cell terminal differentiation mechanism shared by somatic hypermutation and class-switch recombination. Aberrant expression of AID can induce imperfect mutations in non-immunoglobulin genes and was detected in human lymphomas, lung cancer and gastric or intestinal metaplasia. High AID expression is associated with poor prognosis in follicular lymphomas, chronic lymphocytic leukemia and promotes B lymphoid blast crisis in chronic myeloid leukemia. Current study aims to investigate AID expression levels in myeloproliferative neoplasms and their relationship to genetic instability in MPN patients.

Material and methods:

The patient group consisted of 120 patients with bcr-abl negative myeloproliferative neoplasms (PV: 32 patients, ET: 62 patients and PMF: 18 patients, post-ET or post-PV myelofibrosis: 5 patients, unclassified MPN: 1 patient, MPN-AML: 2 patients). The patients were admitted to Istanbul University, Istanbul Medical Faculty, Division of Hematology Outpatient Clinics. The control group consisted of 69 healthy persons. We evaluated AID expression levels of the patients and of the control group. RNA was extracted from peripheral blood samples of patients and controls, RNA was converted to complementary DNA (cDNA). Using the primers and probes of the target gene (AID) and reference gene HPRT (hypoxanthine phosphoribosyltransferase), cDNA was amplified by realtime polymerase chain reaction and expression levels of the genes were evaluated.

Results:

We found that AID expression levels in the patient group were significantly higher than in the control group (Target-AID/Reference-HPRT, mean value: 0. 1747 vs 0. 0417, respectively, p<0. 001). We found that the patients age, blood hemoglobin levels, history of thrombosis, bone marrow reticulin levels, serum LDH levels, organomegaly and having JAK2V617F mutation were not correlated with AID expression levels.

Conclusion:

We showed that AID expression levels in patient with myeloproliferative neoplasms were significantly higher than in healthy control group. The role and the biological significance of high AID expression levels in genetic instability in MPNs need to be elucidated.

Disclosures:

No relevant conflicts of interest to declare.