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Background: Acute myeloid leukemia (AML) patients with various nucleophosmin 1 (NPM1) mutations are controversial in the prognosis. This study aimed to investigate the prognosis of patients according to types of NPM1 mutations (NPM1mut). Methods: Bone marrow samples of 528 patients newly diagnosed with AML, were collected for morphology, immunology, cytogenetics, and molecular biology examinations. Gene mutations were detected by next-generation sequencing (NGS) technology. Results: About 25.2% of cases exhibited NPM1mut. 83.5% of cases were type A, while type B and D were respectively account for 2.3% and 3.0%. Furthermore, 15 cases of rare types were identified, of which 2 cases have not been reported. Clinical characteristics were similar between patients with A-type NPM1 mutations (NPM1A − type mut) and non-A-type NPM1 mutations (NPM1non − A−type mut). Event-free survival (EFS) was significantly different between patients with low NPM1non − A−type mut variant allele frequency (VAF) and low NPM1A − type mut VAF (median EFS = 3.9 vs. 8.5 months, P = 0.020). The median overall survival (OS) of the NPM1non − A−type mutFLT3-ITDmut group, the NPM1A − type mutFLT3-ITDmut group, the NPM1non − A−type mutFLT3-ITDwt group, and the NPM1A − type mutFLT3-ITDwt group were 3.9, 10.7, 17.3 and 18.8 months, while the median EFS of the corresponding groups was 1.4, 5.0, 7.6 and 9.2 months (P < 0.0001 and P = 0.004, respectively). Conclusions: No significant difference was observed in OS and EFS between patients with NPM1A − type mut and NPM1non − A−type mut. However, types of NPM1 mutations and the status of FLT3-ITD mutations may jointly have an impact on the prognosis of AML patients. [ABSTRACT FROM AUTHOR]

Background: With the rapid development of next-generation sequencing (NGS) technologies, researchers are making efforts to reveal the genomic landscape of multiple myeloma (MM). However, the clinical significance of many mutations remains poorly defined due to the genetic heterogeneity of MM. To systematically explore the clinical implications of gene mutations and build practical prognostic models, we performed DNA sequencing in newly diagnosed MM patients. Methods: MM cells were purified from bone marrow aspirates using CD138 microbeads and subjected to sequencing with a 387-gene Panel. Nomogram was developed using Cox's proportional hazards model, and candidate variables were screened by stepwise regression. Internal validation was carried out by the bootstrap method. Results: Between July 2016 and December 2020, a total of 147 patients were included in our study. We found patients with a higher mutational load had a significantly shorter progress-free survival (PFS) (19.0 vs. 32.0 months, P = 0.0098) and overall survival (OS) (3-year OS rates were 66.1% and 80.0%, P = 0.0290). Mutations in chromatin regulators (CRs) including KMT2C (14.3%), KMT2D (14.3%), EP300 (11.6%) and ARID gene family (31.3%) were highly frequent in newly diagnosed MM patients. Interestingly, proteins encoded by these genes could form a complex called KMT2C/D COMPASS (KCDCOMs). Patients with mutations of ARID gene family had a significantly shorter PFS (15.5 vs. 34.0 months, P = 0.0003) and OS (3-year OS rates were 64.9% and 81.0%, P = 0.0351) than patients without ARID gene mutations. Incorporating ARID gene mutations into the current staging system could successfully improve their prognostic performance. The PFS and OS nomogram models (including 1q21 copies, ARID gene mutations, extramedullary disease, mutational load and TP53 mutations) showed good predicting performance in both training and validation sets. Conclusion: Our findings emphasized the importance of CRs mutations in newly diagnosed MM patients and indicated the mutations affecting KCDCOMs might promote the development of MM. High mutational load and harboring mutations in the ARID gene family were novel predictors of adverse prognosis in MM. Prognostic models based on gene mutations were commendably prognostic evaluation methods that could provide a reference for clinical practices. [ABSTRACT FROM AUTHOR]

The study aims to understand geneome diversification and complexity that developed in Acute myeloid leukemia (AML). Next-generation sequencing (NGS) was used to identify the genetic profiles of 22 genes relevant to hematological malignancy in 204 patients with de novo non-M3 AML. At time of initial diagnosis, at least one mutation was identified in 80.9% of patients (165/204). The most commonly mutated gene was NPM1 (22.1%), followed by ASXL1 (18.1%), TET2 (18.1%), IDH2 (15.7%), CEBPA (14.7%), FLT3-ITD (13.2%) and DNMT3A (11.8%). Mutations landscape analysis indicated several patterns of co-occurring and mutual exclusive gene mutations. Some correlation was observed between gene mutations and clinicohematological features. Multivariate analysis showed that age >60 years, karyotypes, IDH2 and KIT mutations were the independent unfavorable prognostic factors for OS; NPM1-mut/ FLT3-ITD-wt was independently correlated with prolonged OS; whereas the independent poor risk factors for RFS were karyotypes, high WBC and RUNX1 mutation. According to different genotype demonstrated by multivariate analysis, 163 patients with intermediate-risk cytogenetics were classified into three subgroups: patients with NPM1-mut/ FLT3-ITD-wt or biallelic CEBPA mutation as favorable risk, patients with KIT, IDH2, TP53 or NRAS mutations as unfavorable risk, and the remaining was the intermediate risk. We also obtain information of clonal evolution during leukemia progression by observing five patients who underwent repeat NGS at relapse in our cohort. NGS techniques is a useful tool for discovering related gene mutations and clonal evolution in AML genomes, leading to novel targeted therapeutic approaches that could improve patients outcomes. [ABSTRACT FROM AUTHOR]

Molecular abnormalities are frequent in core-binding factor (CBF) AMLs, but their prognostic relevance is controversial. Sixty-two patients were retrospectively analyzed and 47 harbored at least one gene mutation with a next-generation-sequencing assay. The most common molecular mutation was KIT mutation (30.6%), followed by NRAS (24.2%) and ASXL1 (14.5%) mutations, which was associated with a higher number of bone marrow blasts (p =.049) and older age (p =.027). The survival analysis showed KIT mutation adversely affected the overall survival (OS) (p =.046). NRAS mutation was associated with inferior OS (p =.016) and RFS (p =.039). Eight patients carried co-mutations of KIT and NRAS and had worse OS (p =.012) and RFS (p =.034). The multivariate analysis showed age ≥60 years and additional chromosomal abnormalities were significant adverse factors for OS. Thus, co-mutations of KIT and NRAS were significantly associated with a poor prognosis and should be taken into account when assessing for prognostic stratification in patients with CBF-AML. [ABSTRACT FROM AUTHOR]

Aim: PAX6 is a transcription factor involved in embryonic development of many organs, including the eyes and the pancreas. Mutations of PAX6 gene is the main cause of a rare disease, congenital aniridia (CA). This case–control study aims to investigate the effects of PAX6 mutations on glucose metabolism and insulin secretion in families with CA. Methods: In all, 21 families with CA were screened by Sanger sequencing. Patients with PAX6 mutations and CA (cases) and age‐matched healthy family members (controls) were enrolled. Oral glucose tolerance test (OGTT) was performed to detect diabetes or impaired glucose tolerance (IGT). Insulin and proinsulin secretion were evaluated. Results: Among 21 CA families, heterozygous PAX6 mutations were detected in five families. Among cases (n = 10) from the five families, two were diagnosed with newly identified diabetes and another two were diagnosed with IGT. Among controls (n = 12), two had IGT. The levels of haemoglobin A1c were 36 ± 4 mmol/mol (5.57 ± 0.46%) and 32 ± 5 mmol/L (5.21 ± 0.54%) in the cases and the controls, respectively (p = 0.049). More importantly, levels of proinsulin in the cases were significantly higher than that of the controls, despite similar levels of total insulin. The areas under the curve of proinsulin in the cases (6425 ± 4390) were significantly higher than that of the controls (3709 ± 1769) (p = 0.032). Conclusion: PAX6 may participate in the production of proinsulin to insulin and heterozygous PAX6 mutations may be associated with glucose metabolism in CA patients. [ABSTRACT FROM AUTHOR]

Abstract: The proto‐oncogene NOTCH1 is frequently mutated in around 10% of patients with chronic lymphocytic leukemia (CLL). This study analyzed NOTCH1 mutation status of 317 Chinese patients with CLL by Sanger sequencing. The frequencies of NOTCH1 mutation in the PEST (proline (P), glutamic acid (E), serine (S), threonine (T)‐rich protein sequence) domain and the 3′ untranslated regions (UTR) were 8.2% and 0.9%, with the most frequent mutation being c.7541_7542delCT and c.*371A>G, respectively. Clinical and biological associations were determined including NOTCH1 mutations with advanced stage (Binet stage, P = 0.010), unmutated immunoglobulin heavy‐chain variable region (IGHV) gene (P < 0.001) and trisomy 12 (+12) (P = 0.014). NOTCH1‐mutated patients had lower CD20 expression intensity than NOTCH1‐unmutated patients (P = 0.029). In addition, NOTCH1‐mutated patients had shorter overall survival (OS) (P = 0.002) and treatment‐free survival (TFS) (P = 0.002) than NOTCH1‐unmutated patients, especially for patients with NOTCH1 c.7541_7542delCT and/or c.*371A>G mutations. Patients with both mutated NOTCH1 and unmutated IGHV had shorter OS (P < 0.001) and TFS (P < 0.001) than those with unmutated NOTCH1 or mutated IGHV. These data provide a comprehensive view of the clinical relevance and prognostic impact of NOTCH1 mutations on Chinese patients with CLL. [ABSTRACT FROM AUTHOR]

The usefulness of flow cytometric variable β-chain repertoire (FC-Vβ) and T-cell receptor gene rearrangement (TCR-GR) analyses for differentiating T-cell large granular lymphocytic leukemia (T-LGLL) from reactive T-large granular lymphocyte (T-LGL) lymphocytosis has been insufficiently studied to date. In this study, we analyzed the diagnostic value of TCR-GR and FC-Vβ analysis in T-LGLL, and compared these results. In our study, FC-Vβ analysis was positive in all cases of T-LGLL, and clonality assessment of FC-Vβ had equal sensitivity and specificity to GeneScanning analysis but was more sensitive than heteroduplex analysis. Suspected T-cell clonality can best be addressed by evaluating two TCR targets (TCRβ and TCRγ), either in parallel or consecutively. Signal transducer and activator of transcription 3 (STAT3) mutation may provide a diagnostic tool for classifying some cases of T-LGL lymphocytosis as true T-LGLL. Our results further demonstrate a significant correlation of STAT3 mutation with pure red cell aplasia, neutropenia, hepatomegaly, β2-microglobulin and anemia. [ABSTRACT FROM AUTHOR]

Abstract: The characteristics of core binding factor (CBF) leukemia appear to differ between Chinese and Caucasian patients. In this study, we analyzed the biological and clinical characteristics of 76 Chinese CBF leukemia patients out of 425 newly diagnosed acute myeloid leukemia (AML) patients. The frequency of CBF AML was 17.9%. Patients harboring t(8;21) were predominant in CBF AML. The incidence of c-kit mutation in CBF AML was 28.9%. The N822K mutation appeared to be more prevalent in Chinese CBF AML patients. Multivariate analysis showed that c-kit mutation and high white blood cell count could negatively impact overall survival (OS) (HR=2.74 and 6.24, P =0.007 and 0.022, respectively) but did not affect relapse-free survival (RFS). Kaplan–Meier analysis showed a significant difference in both OS and RFS between wild-type and mutated c-kit patients. Although we had included recently reported prognostic indicators in our analysis, our results demonstrated that only c-kit mutation and high white blood cell count had prognostic impact on Chinese CBF AML patients. [Copyright &y& Elsevier]