Mutations and deletions of the SUZ12 polycomb gene in myeloproliferative neoplasms

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Combined mutations of ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, RUNX1, TET2 and WT1 genes in myelodysplastic syndromes and acute myeloid leukemias

<p>Abstract</p> <p>Background</p> <p>Gene mutation is an important mechanism of myeloid leukemogenesis. However, the number and combination of gene mutated in myeloid malignancies is still a matter of investigation.</p> <p>Methods</p> <p>We searched for mutations in the <it>ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, RUNX1, TET2 </it>and <it>WT1 </it>genes in 65 myelodysplastic syndromes (MDSs) and 64 acute myeloid leukemias (AMLs) without balanced translocation or complex karyotype.</p> <p>Results</p> <p>Mutations in <it>ASXL1 </it>and <it>CBL </it>were frequent in refractory anemia with excess of blasts. Mutations in <it>TET2 </it>occurred with similar frequency in MDSs and AMLs and associated equally with either <it>ASXL1 </it>or <it>NPM1 </it>mutations. Mutations of <it>RUNX1 </it>were mutually exclusive with <it>TET2 </it>and combined with <it>ASXL1 </it>but not with <it>NPM1</it>. Mutations in <it>FLT3 (</it>mutation and internal tandem duplication), <it>IDH1</it>, <it>IDH2</it>, <it>NPM1 </it>and <it>WT1 </it>occurred primarily in AMLs.</p> <p>Conclusion</p> <p>Only 14% MDSs but half AMLs had at least two mutations in the genes studied. Based on the observed combinations and exclusions we classified the 12 genes into four classes and propose a highly speculative model that at least a mutation in one of each class is necessary for developing AML with simple or normal karyotype.</p

Mutations in ASXL1 are associated with poor prognosis across the spectrum of malignant myeloid diseases

The ASXL1 gene is one of the most frequently mutated genes in malignant myeloid diseases. The ASXL1 protein belongs to protein complexes involved in the epigenetic regulation of gene expression. ASXL1 mutations are found in myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML). They are generally associated with signs of aggressiveness and poor clinical outcome. Because of this, a systematic determination of ASXL1 mutational status in myeloid malignancies should help in prognosis assessment

Targeted deep sequencing improves outcome stratification in chronic myelomonocytic leukemia with low risk cytogenetic features

Clonal cytogenetic abnormalities are found in 20-30% of patients with chronic myelomonocytic leukemia (CMML), while gene mutations are present in >90% of cases. Patients with low risk cytogenetic features account for 80% of CMML cases and often fall into the low risk categories of CMML prognostic scoring systems, but the outcome differs considerably among them. We performed targeted deep sequencing of 83 myeloid-related genes in 56 CMML patients with low risk cytogenetic features or uninformative conventional cytogenetics (CC) at diagnosis, with the aim to identify the genetic characteristics of patients with a more aggressive disease. Targeted sequencing was also performed in a subset of these patients at time of acute myeloid leukemia (AML) transformation. Overall, 98% of patients harbored at least one mutation. Mutations in cell signaling genes were acquired at time of AML progression. Mutations in ASXL1, EZH2 and NRAS correlated with higher risk features and shorter overall survival (OS) and progression free survival (PFS). Patients with SRSF2 mutations associated with poorer OS, while absence of TET2 mutations (TET2wt) was predictive of shorter PFS. A decrease in OS and PFS was observed as the number of adverse risk gene mutations (ASXL1, EZH2, NRAS and SRSF2) increased. On multivariate analyses, CMML-specific scoring system (CPSS) and presence of adverse risk gene mutations remained significant for OS, while CPSS and TET2wt were predictive of PFS. These results confirm that mutation analysis can add prognostic value to patients with CMML and low risk cytogenetic features or uninformative CC

The prevalence of TET2 gene mutations in patients with BCR-ABL-negative myeloproliferative neoplasms (MPN):a systematic review and meta-analysis

SIMPLE SUMMARY: Many molecular biology techniques have been widely used to study the pathogenesis of different diseases, particularly haematologic malignancies which are generally caused by abnormalities in the genome. TET2 gene is one of the commonly found mutated genes in BCR-ABL-negative myeloproliferative neoplasms. However, the prevalence of TET2 gene mutations in the disease remains unclear. Therefore, this study aims to estimate the prevalence of TET2 gene mutations in myeloproliferative neoplasms. The findings may be helpful for future research, diagnoses and the identification of better therapeutic strategies to manage the diseases. ABSTRACT: Multiple recurrent somatic mutations have recently been identified in association with myeloproliferative neoplasms (MPN). This meta-analysis aims to assess the pooled prevalence of TET2 gene mutations among patients with MPN. Six databases (PubMed, Scopus, ScienceDirect, Google Scholar, Web of Science and Embase) were searched for relevant studies from inception till September 2020, without language restrictions. The eligibility criteria included BCR-ABL-negative MPN adults with TET2 gene mutations. A random-effects model was used to estimate the pooled prevalence with 95% confidence intervals (CIs). Subgroup analyses explored results among different continents and countries, WHO diagnostic criteria, screening methods and types of MF. Quality assessment was undertaken using the Joanna Briggs Institute critical appraisal tool. The study was registered with PROSPERO (CRD42020212223). Thirty-five studies were included (n = 5121, 47.1% female). Overall, the pooled prevalence of TET2 gene mutations in MPN patients was 15.5% (95% CI: 12.1–19.0%, I(2) = 94%). Regional differences explained a substantial amount of heterogeneity. The prevalence of TET2 gene mutations among the three subtypes PV, ET and MF were 16.8%, 9.8% and 15.7%, respectively. The quality of the included studies was determined to be moderate–high among 83% of the included studies. Among patients with BCR-ABL-negative MPN, the overall prevalence of TET2 gene mutations was 15.5%

Loss of Asxl1 leads to myelodysplastic syndrome-like disease in mice

ASXL1 is mutated/deleted with high frequencies in multiple forms of myeloid malignancies, and its alterations are associated with poor prognosis. De novo ASXL1 mutations cause Bohring-Opitz syndrome characterized by multiple congenital malformations. We show that Asxl1 deletion in mice led to developmental abnormalities including dwarfism, anophthalmia, and 80% embryonic lethality. Surviving Asxl1(-/-) mice lived for up to 42 days and developed features of myelodysplastic syndrome (MDS), including dysplastic neutrophils and multiple lineage cytopenia. Asxl1(-/-) mice had a reduced hematopoietic stem cell (HSC) pool, and Asxl1(-/-) HSCs exhibited decreased hematopoietic repopulating capacity, with skewed cell differentiation favoring granulocytic lineage. Asxl1(+/-) mice also developed mild MDS-like disease, which could progress to MDS/myeloproliferative neoplasm, demonstrating a haploinsufficient effect of Asxl1 in the pathogenesis of myeloid malignancies. Asxl1 loss led to an increased apoptosis and mitosis in Lineage(-)c-Kit(+) (Lin(-)c-Kit(+)) cells, consistent with human MDS. Furthermore, Asxl1(-/-) Lin(-)c-Kit(+) cells exhibited decreased global levels of H3K27me3 and H3K4me3 and altered expression of genes regulating apoptosis (Bcl2, Bcl2l12, Bcl2l13). Collectively, we report a novel ASXL1 murine model that recapitulates human myeloid malignancies, implying that Asxl1 functions as a tumor suppressor to maintain hematopoietic cell homeostasis. Future work is necessary to clarify the contribution of microenvironment to the hematopoietic phenotypes observed in the constitutional Asxl1(-/-) mice

The Progress of Next Generation Sequencing in the Assessment of Myeloid Malignancies

The introduction and advances on next-generation sequencing have led to novel ways to integrate simultaneous assessment of multiple target genes in routine laboratory analysis. Assessment of myeloid neoplasms with targeted next-generation sequencing panels shows evidence to improve diagnosis, assist therapeutic decisions, provide better information about prognosis, and better detection of minimal residual disease. Herein, we provide information for application and utilization of next-generation sequencing studies with a focus on the most important mutations in acute myeloid leukemia, myelodysplastic syndrome, myeloproliferative neoplasms, and other myelodysplastic/myeloproliferative neoplasms in order to integrate them into the daily clinical practice

FGFR1 amplifi cation and the progression of non-invasive to invasive breast cancer

The incidence of invasive breast cancer (IBC) can be dramatically reduced by improving our abilities to detect and treat ductal carcinoma in situ (DCIS). Progress will be based on a detailed understanding of molecular mechanisms responsible for tumor progression. An interesting study by Jang and colleagues evaluated and compared the frequency of amplification of four oncogenes (HER2, c-MYC, CCND1 and FGFR1) in large cohorts of pure DCIS, in the DCIS component of IBC, and in corresponding IBC. Of particular interest, they found a twofold increase in FGFR1 amplification in IBC versus pure DCIS, and significantly reduced disease-free survival in amplified versus unamplified IBC - leading the authors to conclude that FGFR1 plays an important role in the development and progression of IBC. These observations indeed provide hints that FGFR1 is important in this setting, although the issue is very complex and far from resolved

Mutations of c-Cbl in myeloid malignancies

Next generation sequencing has shown the frequent occurrence of point mutations in the ubiquitin E3 ligase c-Cbl in myeloid malignancies. Mouse models revealed a causal contribution of c-Cbl for the onset of such neoplasms. The point mutations typically cluster in the linker region and RING finger domain and affect both alleles by acquired uniparental disomy. The fast progress in the detection of c-Cbl mutations is contrasted by our scarce knowledge on their functional consequences. The c-Cbl protein displays several enzymatic functions by promoting the attachment of differentially composed ubiquitin chains and of the ubiquitin-like protein NEDD8 to its target proteins. In addition, c-Cbl functions as an adapter protein and undergoes phosphorylation-dependent inducible conformation changes. Studies on the impact of c-Cbl mutations on its functions as a dynamic and versatile adapter protein, its interactomes and on its various enzymatic activities are now important to allow the identification of druggable targets within the c-Cbl signaling network