The Clinical and Molecular Characteristics of FLT3 Mutations in Chinese De Novo Adolescent and Adult Acute Lymphoblastic Leukemia Patients.

BACKGROUND: Activating mutations in FMS-like tyrosine kinase 3 (FLT3) are frequent in acute myeloid leukemia (AML) and have important prognostic and therapeutic implications. FLT3 aberrations have been detected in a smaller fraction of acute lymphoblastic leukemia (ALL), and their prognostic value is not well established. We therefore assessed the FLT3 mutation in Chinese adolescent and adult ALL patients. PATIENTS AND METHODS: We have examined a cohort of 117 Chinese de novo adolescent and adult ALL patients enrolled between June 2016 and June 2017 from the First Affiliated Hospital of Soochow University. Prognostic factors for the ALL patient population were estimated by the Cox regression method. FLT3 mutation was detected by PCR, and its clinical effect was assessed by Kaplan-Meier curves. Differences in FLT3 mutation rate between subgroups were tested by chi-square test. RESULTS: FLT3 mutations accounted for 6.8% (8/117) in our cohort, including 3 internal tandem duplications (2.6%) and 5 tyrosine kinase domains (4.3%, 3 D835Y mutations, 1 M664I mutation, and 1 I867S mutation), which had no clinical significance on either overall survival (OS) or event-free survival. Alterations in FLT3 occurred more often in early thymic precursor (ETP)-ALL compared to non-ETP T-cell acute lymphoblastic leukemia (P = .028). However, the age at onset (P = .004), initial platelet counts (P = .018), and transplantation status (P = .007) were independent prognostic factors of OS for ALL in multivariate analysis. CONCLUSION: The FLT3 mutation was not common in Chinese ALL patients. Age at onset, platelet counts, and transplantation status rather than the presence of the FLT3 mutation were independent prognostic variables for ALL on OS in our cohort. Despite our small sample size, ETP-ALL may indicate a comparable higher FLT3-mutant rate. Because ETP-ALL has been identified as high-risk subgroup, these data warrant clinical studies with the implementation of FLT3 inhibitors in addition to early allogeneic hematopoietic stem-cell transplantation for FLT3-mutant ETP-ALL.

[Clinical characteristics in adult acute myeloid leukemia with isocitrate dehydrogenase gene mutation].

OBJECTIVE: To explore the prevalence and clinical characteristics of isocitrate dehydrogenase (IDH)1 R132 and IDH2 R140/R172 gene mutations in acute myeloid leukemia (AML) patients. METHODS: Polymerase chain reaction (PCR) and direct sequencing were used to sequence exon 4 of IDH gene in 570 AML patients from 2005 to 2011. RESULTS: In a cohort of 570 patients, AML IDH gene mutation was found in 90 (15.79%) patients. IDH1 and IDH2 mutations were detected in 27 (4.74%) patients and 63 (11.05%) patients respectively. None of them had the combined mutations of IDH1 and IDH2. The highest frequency of IDH mutations was found in AML M1 (according to the FAB scheme) compared with all other subtypes (P < 0.01). The median age was 53 years in mutated group versus 40 years in wild-type group (P = 0.010). Mutated and wild-type groups had no significant difference in gender, white blood cell count at diagnosis, hemoglobin count and bone marrow blast percentage, excepting for blood platelets level (median 52×10(9)/L vs 31×10(9)/L, P < 0.01). IDH gene mutations were associated with cytogenetically normal (CN)-AML, NPM1 mutations and particularly with the genotype of mutated NPM1 without FLT3-ITD. IDH gene mutations had no significant correlation with WT1, FLT3-TKD and MLL-PTD mutations. IDH mutated patients had a lower complete remission rate than unmutated in non-M3 patients (58.1% vs 77.9%, P < 0.05). And the patients with mutant IDH gene were associated with a shorter overall survival (28.4% vs 51.3%, P < 0.01). CONCLUSION: IDH gene mutations are more prevalent in elder AML patients and it may constitute a molecular marker for a poor prognosis in AML.

[Clinical significance of common leukemia gene mutations in patients with acute promyelocytic leukemia].

This study was aimed to explore whether multiple common gene mutations of leukemia synergistically involved in acute promyelocytic leukemia (APL) pathogenesis, and to investigate their relevance to clinical features, cytogenetics and molecular risk stratification. 84 specimens of admitted de novo APL patients from February 2005 to October 2010 were collected, the gene mutations of bone marrow mononuclear cells and clinical features of mutation-positive patients were analyzed by genomic DNA-PCR. The results indicated that the prevalence of mutations was 60.7% (51/84), in which the mutations with the highest incidence were found as FLT3-ITD, reaching 27.4% (23/84). Next, there were 12 cases WT1 mutation, 9 for FLT3-TKD, 7 for TET2, 5 for N-RAS, 4 for ASXL1, 2 for EZH2 mutation and 1 positive case in MLL-PTD, IDH1 and CBL mutation respectively. No mutation was found in other JAK1, DNMT3, c-Kit, NPM1, IDH2, RUNX1 and JAK2 (V617F) common leukemia-related genes. Combined analysis with clinical data demonstrated that the patients with FLT3-ITD mutation displayed higher white blood cell counts, while the patients with N-RAS mutation showed lower platelet counts. Overall survival of these patients was obviously shorten as compared with patients with wild-type. This difference between mutant and wild-type of all above mentioned cases was statistically significant (P < 0.05). The difference between APL with simple t (15;17) and additional abnormal karyotype was not statistically significant. It is concluded that the FLT3-ITD mutation is recurrent genetic change in APL, and together with N-RAS mutation indicates poor prognosis. Additional abnormal karyotype does not associate with prognosis of APL.

[Biological characteristics of bone marrow mesenchymal stem cells and JAK2 mutation in myeloproliferative neoplasms].

OBJECTIVE: To study the biological characteristics of bone marrow mesenchymal stem cells (BMSCs) and detect JAK2 mutation in BMSCs from myeloproliferative neoplasms (MPN) patients. METHODS: JAK2 V617F mutation and exon 12 mutation in 70 MPN patients' blood or bone marrow samples were detected. Isolated BMSCs were then characterized their phenotype, mesenchymal differentiation capacity and existence of JAK2 mutation. RESULTS: BMSCs derived from the patients were similar with healthy donors in terms of morphology, surface antigen and differentiation ability. Of them, 38 patients' blood or bone marrow samples harbored JAK2 V617F, and identified that 3 V617F-negative-patients' samples existed JAK2 exon 12. No patients' BMSC harbored JAK2 mutation though their blood or bone marrow samples carried JAK2 mutation. CONCLUSION: BMSCs from MPN patients had similar biological characteristics with healthy donors. BMSCs from MPN patients known to bear JAK2 mutation in blood or bone marrow cells didn't carry the mutation.