Molecular Landscape of Myeloid Neoplasms with Der(1;7)(q10;p10)
Rurika OkudaYotaro OchiKazuhisa ChonabayashiNobuhiro HiramotoMasashi SanadaHiroshi HandaSenji KasaharaShinya SatoNobuhiro KanemuraToshiyuki KitanoMizuki WatanabeWolfgang KernMaria CreignouYuichi ShiraishiMitsumasa WatanabeKensuke UsukiShinsaku ImashukuEva Hellström‐LindbergTorsten HaferlachShigeru ChibaNobuo SezakiLee‐Yung ShihYasushi MiyazakiYoshinori YoshidaTakayuki IshikawaKazuma OhyashikiYoshiko AtsutaYusuke ShiozawaSatoru MiyanoHideki MakishimaYasuhito NannyaSeishi Ogawa
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Both acute myeloid leukemia 1 and c‐Fos are regulatory factors of hematopoietic cell differentiation. We identified that the c‐fos promoter contains an acute myeloid leukemia 1 binding site at nucleotide positions −6–+14. c‐fos promoter activity was induced by transient overexpression of acute myeloid leukemia 1 in Jurkat T‐cells, but not by that of the short form of acute myeloid leukemia 1‐MTG8, a chimeric acute myeloid leukemia 1 protein. In 32Dcl3 myeloid cells, stable overexpression of acute myeloid leukemia 1‐MTG8 blocked the c‐fos gene transcription and cell differentiation, but that of acute myeloid leukemia did not. These data suggest that acute myeloid leukemia 1 and acute myeloid leukemia 1‐MTG8 reciprocally regulate the myeloid cell differentiation, possibly by the way of regulating c‐fos gene transcription.
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Nucleolar phosphoprotein (nucleophosmin 1, NPM1), also known as B23, N038, is located in the nucleolar particles of a multifunctional protein widely expressed in various types of cells. At present, a number of studies found that the NPM1 gene mutation is the most frequent acquired molecular genetic abnormalities in acute myeloid leukemia (AML), especially in normal karyotype AML (nk-AML). NPM1 mutation is a special subgroup in AML, which has relatively unique clinical features, and is the independent prognostic indicators of AML. Research on NPM1 mutation has an important clinical significance in the diagnosis, treatment and prognosis judgment of AML patients. This article reviews the discovery of NPM1 gene mutation in AML in recent years, including structure and physiological functions of NPM1 gene, NPM1 gene mutation in AML, detection methods of NPM1 gene mutation, and so on.
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We investigated the NPM1 mutation status or subcellular expression of NPM protein (nuclear vs. aberrant cytoplasmic) at diagnosis and relapse in 125 patients with acute myeloid leukemia from Italy and Germany. All 52 patients with acute myeloidleukemia carrying at diagnosis mutated or cytoplasmic NPM (NPMc(+) acute myeloid leukemia) retained this feature at relapse. Notably, cytoplasmic mutated NPM has now been retained for eight years in a xenotransplant model of NPMc(+) acute myeloid leukemia in immunodeficient mice. None of 73 acute myeloid leukemia patients carrying at diagnosis wild-type NPM1 gene or showing at immunohistochemistry nucleus-restricted expression of nucleophosmin (NPMc(-) acute myeloid leukemia), which is predictive of NPM1 gene in germline configuration, acquired cytoplasmic mutated NPM at relapse. This finding further confirms that NPMc(+) acute myeloid leukemia represents a primary event rather than a transformation stage of NPMc(-) acute myeloid leukemia. The stability of cytoplasmic mutated NPM in patients with acute myeloid leukemia, even at relapse in extramedullary sites, and in a xenotransplant model, suggest this event is crucial for leukemogenesis and represents the rationale for monitoring minimal residual disease and molecular targeted therapy in NPMc(+) acute myeloid leukemia.
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Acute myeloid leukemia (AML) is a biologically and genetically heterogeneous hematological malignance with an unsatisfactory risk stratification system. Recently, through the novel single-cell RNA sequencing technology, we revealed heterogeneous leukemia myeloblasts in RUNX1-RUNX1T1 AML. Thyrotropin-releasing hormone (TRH), as biomarkers of CD34+CD117bri myeloblasts, were found to be prognostic in RUNX1-RUNX1T1 AML. However, the clinical and genetic features of TRH in AML patients are poorly understood. Here, with data from TCGA AML, TRH was found to be downregulated in patients older than 60 years old, with DNMT3A and NPM1 mutations, while overexpressed in patients with KIT mutations. This was further validated in three other cohorts of primary AML including Beat AML (n = 223), GSE6891 (n = 461), and GSE17855 (n = 237). Furthermore, we demonstrated that the expression of TRH in AML could be used to improve the ELN 2017 risk stratification system. In conclusion, our preliminary analysis revealed that TRH, a novel biomarker for AML patients, could be used to evaluate the survival of AML.
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NPM1-mutated myeloid neoplasms (NPM1+ MNs) with <20% blood or bone marrow blasts are rare and have been previously shown in limited case series to exhibit an aggressive clinical course. We assembled the largest cohort of NPM1+ MN cases to date (n = 45) and compared it with NPM1- MN (n = 95) and NPM1+ de novo acute myeloid leukemia (AML; n = 119) patients. Compared with NPM1- MN, NPM1+ MN were associated with younger age (P = .007), a normal karyotype (P < .0001), more frequent mutations involving DNMT3A (P = .01) and PTPN11 (P = .03), and fewer involving ASXL1 (P = .003), RUNX1 (P = .0004), and TP53 (P = .02). Mutations involving IDH1 or IDH2 (IDH1/2) (P = .007) and FLT3 (internal tandem duplication, P < .0001; noninternal tandem duplication, P = .01) were less frequent in NPM1+ MN than in NPM1+ AML. In multivariable analyses performed in patients with myelodysplastic syndrome only, total mutation count (hazard ratio [HR], 1.3; P = .05), NPM1 mutation (HR, 3.6; P = .02), TP53 mutation (HR, 5.2; P = .01), and higher International Prognostic Scoring System-R score (HR, 1.7; P = .0003) were independently associated with shorter overall survival, whereas stem cell transplant conferred a favorable effect (HR, 0.1; P < .0001). These data suggest that NPM1+ MN are biologically distinct from NPM1- MN. Similar to NPM1+ AML, patients with NPM1-mutated myelodysplastic syndrome may benefit from more intensive therapeutic regimens.
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