Xiaoyan Ke

High expression of RUNX1 is associated with poorer outcomes in cytogenetically normal acute myeloid leukemia

Depending on its expression level, RUNX1 can act as a tumor promoter or suppressor in hematological malignancies. The clinical impact of RUNX1 expression in cytogenetically normal acute myeloid leukemia (CN-AML) remained unknown, however. We evaluated the prognostic significance of RUNX1 expression using several public microarray datasets. In the testing group (n = 157), high RUNX1 expression (RUNX1high) was associated with poorer overall survival (OS; P = 0.0025) and event-free survival (EFS; P = 0.0025) than low RUNX1 expression (RUNX1low). In addition, the prognostic significance of RUNX1 was confirmed using European Leukemia Net (ELN) genetic categories and multivariable analysis, which was further validated using a second independent CN-AML cohort (n = 162, OS; P = 0.03953). To better understand the mechanisms of RUNX1, we investigated genome-wide gene/microRNAs expression signatures and cell signaling pathways associated with RUNX1 expression status. Several known oncogenes/oncogenic microRNAs and cell signaling pathways were all up-regulated, while some anti-oncogenes and molecules of immune activation were down-regulated in RUNX1high CN-AML patients. These findings suggest RUNX1high is a prognostic biomarker of unfavorable outcome in CN-AML, which is supported by the distinctive gene/microRNA signatures and cell signaling pathways.

A minicircuitry of microRNA-9-1 and RUNX1-RUNX1T1 contributes to leukemogenesis in t(8;21) acute myeloid leukemia

MicroRNA‐9‐1(miR‐9‐1) plays an important role in the mechanism that regulates the lineage fate of differentiating hematopoietic cells. Recent studies have shown that miR‐9‐1 is downregulated in t (8; 21) AML. However, the pathogenic mechanisms underlying miR‐9‐1 downregulation and the RUNX1‐RUNX1T1 fusion protein, generated from the translocation of t (8; 21) in AML, remain unclear. RUNX1‐RUNX1T1 can induce leukemogenesis through resides in and functions as a stable RUNX1‐RUNX1T1‐containing transcription factor complex. In this study, we demonstrate that miR‐9‐1 expression increases significantly after the treatment of RUNX1‐RUNX1T1 (+) AML cell lines with decitabine (a DNMT inhibitor) and trichostatin A (an HDAC inhibitor). In addition, we show that RUNX1‐RUNX1T1 triggers the heterochromatic silencing of miR‐9‐1 by binding to RUNX1‐binding sites in the promoter region of miR‐9‐1 and recruiting chromatin‐remodeling enzymes, DNMTs, and HDACs, contributing to hypermethylation of miR‐9‐1 in t (8; 21) AML. Furthermore, because RUNX1, RUNX1T1, and RUNX1‐RUNX1T1 are all regulated by miR‐9‐1, the silencing of miR‐9‐1 enhances the oncogenic activity of these genes. Besides, overexpression of miR‐9‐1 induces differentiation and inhibits proliferation in t (8; 21) AML cell lines. In conclusion, our results indicate a feedback circuitry involving miR‐9‐1 and RUNX1‐RUNX1T1, contributing to leukemogenesis in RUNX1‐RUNX1T1 (+) AML cell lines.

High expression of MAP7 predicts adverse prognosis in young patients with cytogenetically normal acute myeloid leukemia.

Microtubule-associated protein 7 (MAP7) plays an important role in cancer cells. In this study, we identified the prognostic significance of MAP7 expression in cytogenetically normal acute myeloid leukemia (CN-AML) patients (aged <60 years) based on several microarray datasets. In the first group (n = 129), high MAP7 expression (MAP7high) was associated with adverse overall survival (OS; P = 0.0441) and event-free survival (EFS; P = 0.0114) compared with low MAP7 expression (MAP7low). In addition, the prognostic significance of MAP7 was confirmed by European Leukemia Net (ELN) intermediate-I genetic categories and multivariable analysis. In the second independent group of CN-AML patients (aged <60 years), MAP7high was also associated with adverse OS (n = 88, OS; P = 0.00811). To understand the inherent mechanisms of MAP7’s prognosis, we investigated genome-wide gene/microRNA expression signatures associated with MAP7 expression. Several known oncogenic genes/microRNAs and anti-oncogenic genes/microRNAs were disordered in MAP7high CN-AML patients. In conclusion, MAP7high is an adverse prognostic biomarker for CN-AML, which may be attributed to the distinctive genome-wide gene/microRNA expression and related cell signaling pathways.

Prognostic significance of microRNA-99a in acute myeloid leukemia patients undergoing allogeneic hematopoietic stem cell transplantation

Overexpression of microRNA-99a (miR-99a) have been associated with adverse prognosis in acute myeloid leukemia (AML). Nevertheless, whether it also predicts poor outcome in post-allogeneic hematopoietic stem cell transplantation (allo-HSCT) AML patients remains unclear. To further elucidate the prognostic value of miR-99a, 74 AML patients with miR-99a expression report who underwent allo-HSCT from The Cancer Genome Atlas database were identified and grouped into either miR-99ahigh or miR-99alow based on their miR-99a expression levels relative to the median. Two groups had similar clinical and molecular characteristics except that miR-99ahigh group had fewer patients of the French-American-British M4 subtype (P = 0.018) and more frequent CEBPA mutations (P = 0.005). Univariate analysis indicated that high miR-99a expression was unfavorable for both event-free survival (EFS) and overall survival (OS; P = 0.029; P = 0.012, respectively). Multivariate analysis suggested that high miR-99a expression was an independent risk factor for both EFS and OS in AML patients who underwent allo-HSCT [hazard ratio (HR) 1.909, 95% confidence interval (CI) 1.043–3.494, P = 0.036 and HR 2.179, 95% CI 1.192–3.982, P = 0.011, respectively]. Our results further proved that high miR-99a expression could predict worse outcome in AML patients, even in those who underwent intensive post-remission therapy such as allo-HCST.

BAALC and ERG expression levels at diagnosis have no prognosis impact on acute myeloid leukemia patients undergoing allogeneic hematopoietic stem cell transplantation

Brain and acute leukemia, cytoplasmic (BAALC) and ETS-related gene (ERG) expression levels are independent prognostic factors for acute myeloid leukemia (AML); however, their prognostic impacts on AML patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) require further investigation. We studied 71 de novo AML patients treated with allo-HSCT and defined low and high expressers according to the median expression levels of BAALC and ERG at diagnosis respectively. High BAALC expression was associated with wild-type NPM1 (P = 0.000) and RUNX1 mutations (P = 0.027). High ERG expression was associated with FLT3-ITD absence (P = 0.003) and wild-type NPM1 (P = 0.001). BAALC and ERG expression levels were significantly correlated with each other (P = 0.001). Survival analyses including Kaplan-Meier curves and univariate and multivariate analysis consistently reported that there were no significant differences for both event-free survival (EFS) and overall survival (OS) (all P > 0.1), between high versus low BAALC and ERG expressers. Our study suggested that despite of their well-known adverse role in prognosis of AML, neither BAALC nor ERG expression levels at diagnosis had effect on survival of AML patients who underwent allo-HSCT.

Combining retinoic acid and oral arsenic may be potentially the first-line therapy for non-high-risk acute promyelocytic leukemia

Once regarded as a rapidly fatal disease, acute promyelocytic leukemia (APL) is now curable in most cases with the use of targeted treatment alone and without chemotherapy (CHT) (1). Platzbecker et al . (2) reported a prospective, randomized, multicenter, open-label, phase III noninferiority trial, which demonstrated the advantages of all-trans-retinoic acid (ATRA) and intravenous ATO over ATRA and CHT with significantly greater and more sustainable antileukemic efficacy over time for non-high-risk APL. The recent paper by Iland et al . (3) also revealed that ATRA and arsenic in initial therapy induction and consolidation for APL reduced the risk of relapse compared with historical controls. These studies demonstrated the advantages of combining ATRA and intravenous ATO over ATRA and CHT for non-high-risk APL.

Comparison of Clinical Efficacy of Cytarabine with Different Regimens in Postremission Consolidation Therapy for Adult t(8;21) AML Patients: A Multicenter Retrospective Study in China

Background: The survival of patients with acute myeloid leukemia (AML) with t(8;21) was reported to be shorter in China than in other countries. Patients: We analyzed the correlation between different cytarabine (Ara-c) regimens and outcome in 255 t(8;21) AML patients in China who received postremission consolidation chemotherapy only. Results: The 5-year overall survival (OS) of the high-dose Ara-c group (HDAC; 2≤ Ara-c ≤3 g/m2), intermediate-dose Ara-c group (MDAC; 1.0≤ Ara-c <2.0 g/m2), low-dose Ara-c group (LDAC; 0.2< Ara-c <1.0 g/m2) and standard-dose Ara-c group (SDAC; 0.1≤ Ara-c ≤0.2 g/m2) were 65.3, 39.4, 25.2 and 27.9%, respectively (p = 0.003). In the HDAC group, but not in the MDAC group, the 5-year OS of patients who achieved 3-4 cycles of chemotherapy was superior to those who underwent 1-2 cycles (84.4 vs. 43.6%, p < 0.05), and the 3-year OS of patients who achieved an accumulated 36 g/m2 of Ara-c was significantly higher compared to those who did not (85.3 vs. 39.2%, p < 0.05). Multivariate analysis indicated that factors such as WBC >3.5 × 109/l, PLT ≤30 × 109/l, and extramedullary infiltration were associated with a poor prognosis. Conclusion: The survival of t(8;21) AML patients treated with high-dose Ara-c (≥2 g/m2) was superior to other dose levels in postremission consolidation chemotherapy. Patient survival was improved by 3-4 cycles of chemotherapy with an accumulated concentration of 36 g/m2 of Ara-c. WBC >3.5 × 109/l, PLT ≤30 × 109/l and extramedullary infiltration could be indicative of a poor clinical prognosis.

Clinical and biological implications of IDH1/2 in acute myeloid leukemia with DNMT3A mut

Purpose The incidence of DNMT3A mutations in acute myeloid leukemia (AML) is quite high and often confers a poorer prognosis. Another common gene involved in AML is IDH1/2. However, the influence of IDH1/2 mutations on outcomes in DNMT3A-mutated patients remains unknown. This study aims to determine the effect of IDH1/2mut on the prognosis in patients with DNMT3A-mutated AML. Patients and methods We screened patients from The Cancer Genome Atlas database and selected 51 patients with AML and the DNMT3A mutation, among which 16 patients (31.4%) had both DNMT3A and IDH1/2mut. Results Among our sample, 11 cases had the IDH1 mutation (21.7%), and 5 cases had the IDH2 mutation (9.8%). Patients in the DNMT3AmutIDH1/2wild group showed a greater number of NPM1 mutation (P=0.022), and higher event-free survival (EFS) and overall survival (OS) after hematopoietic stem cell transplantation (HSCT) (P=0.010 and P=0.007, respectively). Patients in the DNMT3AmutIDH1/2mut group showed no increase in EFS or OS after HSCT or chemotherapy. Other factors, like white blood cells, bone marrow blasts, peripheral blood blasts, and mutated recurrent gene numbers had no significant influence on EFS and OS. Conclusion The IDH1/2 gene had little influence on the prognosis of patients with the DNMT3A mutation. For patients in the DNMT3AmutIDH1/2wild group, HSCT had a more favorable therapeutic effect. For patients with DNMT3A and IDH1/2mut, chemotherapy and HSCT appeared to have similar efficacy.

Biological and clinical influences of NPM1 in acute myeloid leukemia patients with DNMT3A mutations

Purpose DNMT3A and NPM1 mutations are known to impact the prognosis of acute myeloid leukemia (AML). DNMT3A mutations are negative prognostic factors, while NPM1 mutations are low-risk factors and inclined to concurrently appear with DNMT3A mutations. In this study, we aimed to find out how NPM1 mutations affect patients’ outcomes in the background of DNMT3A mutations. Patients and methods We screened The Cancer Genome Atlas (TCGA) database and found 51 AML patients with DNMT3A mutations. Of them, 28 patients had a combination of NPM1 mutations. Results In all, NPM1 had the highest mutation frequency (n=28, 54.9%). DNMT3Amut/NPM1mut patients had higher bone marrow (BM) blasts (P=0.015), higher FLT3-ITD/TKD rate (P=0.004), and lower IDH2 mutation rate (P=0.014) than the DNMT3Amut/NPM1wild patients, while their prognoses were the same as the DNMT3Amut/NPM1wild patients (P>0.1). All 51 patients benefited from hematopoietic stem cell transplantation (HSCT) treatment (P=0.005 and 0.001 for event-free survival [EFS] and overall survival [OS], respectively). In the 23 patients with DNMT3Amut/NPM1wild, those who received HSCT had prolonged EFS and OS (P=0.043 and 0.008, respectively), while HSCT treatment did not produce a positive impact on EFS and OS in the remaining 28 patients with DNMT3Amut/NPM1mut (P=0.056 and 0.053, respectively). Conclusion Our study found that NPM1 mutations influenced BM blasts’ percentage, FLT3-ITD/TKD rate, and IDH2 mutation rate in AML patients with DNMT3A mutations but made little difference to the overall prognosis. While HSCT treatments benefited all DNMT3Amut patients, it was better for DNMT3Amut/NPM1wild patients to extend their EFS and OS.

Mutational spectrum and prognostic stratification of intermediate-risk acute myeloid leukemia

The mutational spectrum and prognostic stratification of intermediate-risk acute myeloid leukemia (IR-AML), which accounts for a substantial number of AML, are unclear. In order to explore the prognostic significance of the mutational spectrum in IR-AML, 106 IR-AML patients were collected from The Cancer Genome Atlas database. Sixty-two patients underwent chemotherapy-only, forty-four proceeded to allogeneic hematopoietic stem cell transplantation (allo-HSCT). Fifty-five patients had more than five recurrent genetic mutations. NPM1 had the highest mutation frequency, followed by DNMT3A, FLT3, RUNX1, IDH2, IDH1, and TET2. In all patients, allo-HSCT was an independent favorable factor for EFS and OS (P = 0.036, P = 0.001, respectively); age ≥60 years, FLT3-ITD and mutations in DNMT3A and RUNX1 were independent risk factors for survival (all P < 0.05). In the chemotherapy-only group, multivariate analysis showed that age ≥60 years was an independent risk factor for EFS and OS (P = 0.008, P = 0.017, respectively). In the allo-HSCT group, multivariate analysis indicated that MLL-PTD was an independent risk fact for EFS (P = 0.037), FLT3-ITD and RUNX1 mutations independently contributed to poor OS (P = 0.035, P = 0.014, respectively). In conclusion, older age was an important risk factor for IR-AML patients undergoing chemotherapy-only; FLT3-ITD, MLL-PTD and RUNX1 mutations were significant risk factors for IR-AML patients who received allo-HSCT.