RUNX1 mutation and elevated FLT3 gene expression cooperates to induce inferior prognosis in cytogenetically normal acute myeloid leukemia patients

Abstract

Background Acute myeloid leukemia (AML) is a bone marrow malignancy having multiple molecular pathways driving its progress. In recent years, the main causes of AML considered all over the world are genetic variations in cancerous cells. The RUNX1 and FLT3 genes are necessary for the normal hematopoiesis and differentiation process of hematopoietic stem cells into mature blood cells, therefore they are the most common targets for point mutations resulting in AML. Methods We screened 32 CN-AML patients for FLT3-ITD (by Allele-specific PCR) and RUNX1 mutations (by Sanger sequencing). The FLT3 mRNA expression was assessed in all AML patients and its subgroups. Results Eight patients (25%) carried RUNX1 mutation (K83E) while three patients (9.37%) were found to have internal tandem duplications in FLT3 gene. The RUNX1 mutation data were correlated with clinical parameters and FLT3 gene expression profile. The RUNX1 mutations were observed to be significantly prevalent in older males. Moreover, RUNX1 and FLT3-mutated patients had lower complete remission rate, event-free survival rate, and lower overall survival rate than patients with wild-type RUNX1 and FLT3 gene. The RUNX1 and FLT3 mutant patients with up-regulated FLT3 gene expression showed even worse prognosis. Bradford Assay showed that protein concentration was down-regulated in RUNX1 and FLT3 mutants in comparison to RUNX1 and FLT3 wild-type groups. Conclusion This study constitutes the first report from Pakistan reporting significant molecular mutation analysis of RUNX1 and FLT3 genes including FLT3 expression evaluation with follow-up. This provides an insight that aforementioned mutations are markers of poor prognosis but the study with a large AML cohort will be useful to further investigate their role in disease biology of AML.

Clinical Outcomes of Acute Myeloid Leukemia Patients Harboring the RUNX1 Mutation: Is It Still an Unfavorable Prognosis? A Cohort Study and Meta-Analysis

“…The 225 remaining articles underwent full-length article reviews. In total, 24 studies were eventually included in our meta-analysis: 12 prospective studies [ 9 , 13 , 14 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ], 11 retrospective studies [ 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ]), and our prospective cohort study. Supplementary Data S5 illustrates the literature review and article selection process.…”

“…For RFS, the RR was 1.37 (95% CI: 1.04–1.80; I 2 = 59%; p = 0.03; Figure 3 A) [ 9 , 13 , 29 , 33 , 34 , 37 , 38 , 39 , 42 , 44 ]. For EFS, the RR was 1.37 (95% CI: 1.13–1.66; I 2 = 49%; p = 0.002; Figure 3 B) [ 9 , 13 , 30 , 32 , 35 , 36 , 37 , 41 , 43 , 46 ].…”

“…To better understand the clinical outcomes of AML with RUNX1 mut , we focused on AML patients who did not have these dismal prognostic factors. Three subgroup analyses were performed: intermediate-risk cytogenetics, de novo AML, and de novo AML with intermediate-risk cytogenetics [ 14 , 28 , 29 , 30 , 31 , 33 , 34 , 35 , 36 , 37 , 38 , 41 , 42 , 44 , 46 ].…”

Venetoclax plus azacitidine and donor lymphocyte infusion in treating acute myeloid leukemia patients who relapse after allogeneic hematopoietic stem cell transplantation

“…Then further analysis revealed that there was no difference regarding EFS and OS between patients with first-class mutation and patients without first-class mutation. As known, the first-class mutations included prognostic genes such as CEBPA, FLT3, DNMT3A, NPM1, and RNF213; they are previously observed to correlate with prognosis of AML [ 28 – 30 ]. However, our study indicated that the mutated genes might not be correlated with survival in patients with relapsed AML after allo-HSCT, which might result from the reduced small sample size in our study; this presumption needed more validation by future studies.…”

Clinical characteristics and prognosis of acute myeloid leukemia patients with Runt‐related transcription factor 1 mutation: A single‐center retrospective analysis

“…However, the median age of AML-RUNX1 mut in prior studies was 56.5-70.5 years. 2,4,[22][23][24][25][26] In our study, AML-RUNX1 mut were characterized by a younger demographic which might contribute to a higher proportion of receiving intensive chemotherapy. Notably, the induction treatment protocols A previous study has already indicated that the strategic selection of intensive chemotherapy regimens plays a significant role in achieving higher CR rates.…”