The affect of asxl1 gene mutations on clinical course and prognosis of myeloproliferative neoplasms

Aims: Chronic myeloproliferative neoplasms (MPN) are a group of disorders characterized by clonal proliferation in all three cell lines. One of the disorder in this group, namely chronic myelogenous leukemia (CML), develops from Philadelphia chromosome and its oncogene BCR-ABL. CML has different clinical features. Ph (-) MPN is grouped as primary polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). While increased red blood cell mass is defined as PV, increased number of platelets is called ET. PMF is characterized by the increased bone marrow fibrosis. In 2005 with the definition of the JAK-2 V617F mutation, it became possible to demonstrate the clonal growth in 95-98% of patients with PV, and almost 50% of patients with ET and PMF. Later on, JAK exon 12 mutations in PV patients, MPL W515L/K and CALR (calreticulin) mutations have been identified in ET and PMF patients. One of the mutations shown in MPN patients is the ASXL 1 gene mutations. ASXL 1 (Additional sex comb like1), ASXL 2 ( Additional sex comb like 2) and ASXL 3 (Additional sex comb like 3) are associated with gene Asx (Drosophila melanogaster additional sex combs) which suppresses the HOX gene. ASXL1 gene mutations are generally present in the form of shift mutations located in exon 12 of the gene and have the loss of PHD (plant homeofinger domain) at the carboxy terminus. The incidence of ASXL 1 gene mutations are in PV 2-7%, in ET 0-10%, in PMF 13-32%. ASXL1 gene mutations make some changes in the pathogenesis and cancer biology of myeloproliferative disease. The mutations are negatively impact the prognosis and some studies suggest a more aggressive therapeutic approach in patients who have ASXL1 gene mutations. In this study, we investigated the frequency of ASXL1 gene mutations of 103 Ph(-) MPN patients and how ASXL1 gene mutations affect clinical course and prognosis of the patients followed in T.C. Istanbul Bilim University Department of Hematology. Materials and Methods : Totaly 103 MPN patients were enrolled in this study. This study was approved by the Clinical Research Ethics Committee of Istanbul Bilim University. After obtaining informed consent from the patients, we performed DNA isolation from the blood that were kept in EDTA tubes. ASXL1 gene mutation analysis were done by DNA sequence analysis method. Results were evaluated and Fisher reality test, chi-square test, odds ratio and Tukey's multiple comparison tests were performed for statistical analysis. Results: ASXL1 gene mutations were identified in 6 patients in our cohort. These mutations were found as %6,25 (3/48) in ET, %4,35'(2/46) in PV and %11,11(1/9) in PMF patients. When exon 12 of ASXL1 gene mutations were scanned, the most common mutation was c.1934dupG (p.g646TrpfsX12) and the second was c.1954G.a (p.G652S), these are the most common types of ASXL1 gene mutations. The mutation ASXL1 c.1934 dupG (p.g646TrpfsX12) was found in 3 of ET patients (%6,25) and 1 of PV patients (%2,22). The mutation of c.1954g.a (p.G652S) was found in 1 of PV patients (%2,17) and 1 of PMF patients (%12,5). While the average baseline hemoglobin and platelet values were higher, the average baseline neutrophil and leukocytes were lower in the group with ASXL1 gen mutations than the other group. Splenomegaly was found to be lower and the rate of thrombosis (especially arterial thrombosis) was found to be higher in the group with ASXL1 gene mutations. In our cohort that were followed up for 4,1 years, non-hematologic cancer rates (solid tumors) were found to be quite high (%14,5). Eightly percent of these patients have JAK-2 V617F mutation. Two of these patients with JAK-2 V617F mutation have also ASXL1 c.1954G.a (p.G652S) gene mutation. Conclusion: Consistent with the literature ASXL1 gene mutations are most common in PMF patients than ET and PV patients. The mean age was higher in the group with ASXL1 gene mutations. In our cohort the most common types of in ASXL1 genes were c.1934dupG (p.g646TrpfsX12) (4/6) and c.1954G.a (p.G652S) (2/6). Thrombosis (especially arterial thrombosis) was found to be higher in the patient with ASXL1 gene mutations. In our cohort non-hematologic cancer (solid tumors) rates were found to be higher (%14,5). Two of the patients with non-hematologıc cancer were found to have both JAK-2 V617F gene mutation and ASXL1 c.1954G.a (p.G652S) gene mutation. In our cohort, five of the patients had used hydroxyurea after the diagnosis of MPN and then they had non-hematological cancers. On the other hand, after the diagnosis of MPN disease, two of the patients who did not use hydroxyurea have had non-hematologic cancer (solid tumors). So we suggest that not only using hydroxyurea but also the other factors may cause non-hematologic cancers (solid tumors) in patients with MPN.