Clinical implications of recurrent gene mutations in acute myeloid leukemia

Yu, Jifeng; Li, Yingmei; Zhang, Danfeng; Wan, Dingming; Jiang, Zhongxing

doi:10.1186/s40164-020-00161-7

Cited by 55 publications

(39 citation statements)

References 124 publications

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“…These mutations are also present in 20% of patients with myelodysplastic/myeloproliferative neoplasm (MDS/MPN) [ 41 ] and in 15% of patients with chronic myeloid leukemia (CLL) [ 58 – 60 ] . More recently, SF3B1 mutations have been identified at relatively high frequency in some solid tumors, such as various pigmented tumors, including uveal melanoma (UM) [ 61 , 62 ], mucosal melanoma [ 63 ], leptomeningeal melanoma [ 64 ] and blue nevus-like cutaneous melanoma [ 65 ], and neuroblastomas that arise following chromothripsis [ 66 ], estrogen receptor-positive breast cancers (BC) [ 67 ], pancreatic ductal adenocarcinoma [ 68 ], prostate cancer [ 69 ], prolactinomas [ 70 ], acute myeloid leukemia [ 71 , 72 ], and many others [ 73 – 75 ].…”

Section: Sf3b1 Mutations In Cancermentioning

confidence: 99%

The biological function and clinical significance of SF3B1 mutations in cancer

et al. 2020

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Spliceosome mutations have become the most interesting mutations detected in human cancer in recent years. The spliceosome, a large, dynamic multimegadalton small nuclear ribonucleoprotein composed of small nuclear RNAs associated with proteins, is responsible for removing introns from precursor mRNA (premRNA) and generating mature, spliced mRNAs. SF3B1 is the largest subunit of the spliceosome factor 3b (SF3B) complex, which is a core component of spliceosomes. Recurrent somatic mutations in SF3B1 have been detected in human cancers, including hematological malignancies and solid tumors, and indicated to be related to patient prognosis. This review summarizes the research progress of SF3B1 mutations in cancer, including SF3B1 mutations in the HEAT domain, the multiple roles and aberrant splicing events of SF3B1 mutations in the pathogenesis of tumors, and changes in mutated cancer cells regarding sensitivity to SF3B small-molecule inhibitors. In addition, the potential of SF3B1 or its mutations to serve as biomarkers or therapeutic targets in cancer is discussed. The accumulated knowledge about SF3B1 mutations in cancer provides critical insight into the integral role the SF3B1 protein plays in mRNA splicing and suggests new targets for anticancer therapy.

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Section: Sf3b1 Mutations In Cancermentioning

confidence: 99%

The biological function and clinical significance of SF3B1 mutations in cancer

et al. 2020

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“…Some of these, called “High Molecular Risk” (HMR) mutations (e.g., in ASXL1 and SRSF2 ), are associated with a worse prognosis and leukemic transformation 4 . Moreover, other pathogenic variants affecting genes such as TET2 , TP53 , and FLT3 are related to preleukemic and leukemic conditions 5 .…”

Section: Introductionmentioning

confidence: 99%

Mutated clones driving leukemic transformation are already detectable at the single-cell level in CD34-positive cells in the chronic phase of primary myelofibrosis

et al. 2021

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Disease progression of myeloproliferative neoplasms is the result of increased genomic complexity. Since the ability to predict disease evolution is crucial for clinical decisions, we studied single-cell genomics and transcriptomics of CD34-positive cells from a primary myelofibrosis (PMF) patient who progressed to acute myeloid leukemia (AML) while receiving Ruxolitinib. Single-cell genomics allowed the reconstruction of clonal hierarchy and demonstrated that TET2 was the first mutated gene while FLT3 was the last one. Disease evolution was accompanied by increased clonal heterogeneity and mutational rate, but clones carrying TP53 and FLT3 mutations were already present in the chronic phase. Single-cell transcriptomics unraveled repression of interferon signaling suggesting an immunosuppressive effect exerted by Ruxolitinib. Moreover, AML transformation was associated with a differentiative block and immune escape. These results suggest that single-cell analysis can unmask tumor heterogeneity and provide meaningful insights about PMF progression that might guide personalized therapy.

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“…It is characterized by malignant clonal hematopoietic stem/progenitor cell disease. About 70–90% MDS patients has one or more gene mutations 1 – 3 . A number of studies have confirmed that gene mutations play important role in the occurrence, development, treatment and prognosis in MDS patients 2 – 6 .…”

Section: Introductionmentioning

confidence: 99%

Differential U2AF1 mutation sites, burden and co-mutation genes can predict prognosis in patients with myelodysplastic syndrome

Wang

Guo

Dong

et al. 2020

Sci Rep

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To investigate the U2AF1 gene mutation site, mutation load and co-mutations genes in patients with myelodysplastic syndrome (MDS) and their effects on prognosis. Gene mutation detection by next-generation sequence and related clinical data of 234 MDS patients were retrospectively collected and analyzed for the relationship between the clinical characteristics, treatment efficacy and prognosis of U2AF1 gene mutation. Among the 234 MDS patients, the U2AF1 gene mutation rate was 21.7% (51 cases), and the median variant allele frequency was 39.5%. Compared with the wild type, the U2AF1 mutant had a higher incidence of chromosome 8 aberration, and was positively correlated with the occurrence of ASXL1, RUNX1, SETBP1 gene mutation, negatively correlated with SF3B1, NPM1 genes mutation (p < 0.05). The most common mutation site of U2AF1 was S34F (32 cases), while U2AF1 Q157P site mutations had a higher incidence of chromosome 7 abnormalities (p = 0.003). The U2AF1 gene mutation more frequently coincided with signal pathway related gene mutations (p = 0.043) with a trend of shortened overall survival. Among patients with U2AF1 gene mutations, those with ASXL1 mutations were prone to develop into acute myeloid leukemia, those with RUNX1 mutations had an increased risk of relapse, and those with TET2 mutations had higher 1-year survival rate. Compared with the patient group of lower mutation load (VAF ≤ 40%), the group with higher mutation load of U2AF1 (VAF > 40%) had a significantly lower 1-year survival rate (46.1% and 80.5%, p = 0.027). The criteria of U2AF1 VAF > 40% is an independent indicator for poor prognosis of MDS patients. VAF > 40% of U2AF1 is an independent factor of short OS in MDS patients. MDS patients with a mutation in the Q157P site of U2AF1 and a higher U2AF1 mutation load suggests poor prognosis, and co-mutated genes in U2AF1 can affect disease progression and prognosis.

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Clinical implications of recurrent gene mutations in acute myeloid leukemia

Cited by 55 publications

References 124 publications

The biological function and clinical significance of SF3B1 mutations in cancer

The biological function and clinical significance of SF3B1 mutations in cancer

Mutated clones driving leukemic transformation are already detectable at the single-cell level in CD34-positive cells in the chronic phase of primary myelofibrosis

Differential U2AF1 mutation sites, burden and co-mutation genes can predict prognosis in patients with myelodysplastic syndrome

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