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Acute myeloid leukemia (AML) with nucleophosmin 1 (NPM1) mutations exhibits distinct biological and clinical features, accounting for approximately one-third of AML. Recently, the N6-methyladenosine (m6A) RNA modification has emerged as a new epigenetic modification to contribute to tumorigenesis and development. However, there is limited knowledge on the role of m6A modifications in NPM1-mutated AML. In this study, the decreased m6A level was first detected and high expression of fat mass and obesity-associated protein (FTO) was responsible for the m6A suppression in NPM1-mutated AML. FTO upregulation was partially induced by NPM1 mutation type A (NPM1-mA) through impeding the proteasome pathway. Importantly, FTO promoted leukemic cell survival by facilitating cell cycle and inhibiting cell apoptosis. Mechanistic investigations demonstrated that FTO depended on its m6A RNA demethylase activity to activate PDGFRB/ERK signaling axis. Our findings indicate that FTO-mediated m6A demethylation plays an oncogenic role in NPM1-mutated AML and provide a new layer of epigenetic insight for future treatments of this distinctly leukemic entity.

Additional file 12 : Figure S7. HOTAIRM1 expression in the different transfected cells. a-b HOTAIRM1 expression in HOTAIRM1-silenced (a) and HOTAIRM1-enforced OCI-AML3 cells (b). c-d HOTAIRM1 expression in HOTAIRM1-silenced (c) as well as HOTAIRM1-enforced OCI-AML2 + NPM1-mA cells (d). e HOTAIRM1 expression in HOTAIRM1-enforced OCI-AML2 cells.

Additional file 4 : Table S4. The top 10 predicted factors bound to HOTAIRM1 promoter by JASPAR database analysis.

Additional file 3 : Table S3. Primers used for ChIP-qPCR.

Additional file 6 : Figure S1. Stable NPM1-mA-GFP expressing OCI-AML2 cells (OCI-AML2 + NPM1-mA) were generated. a Cytoplasmic localization of NPM1-mA in the OCI-AML2 stably expressing Flag-GFP tagged NPM1-mA. Cytospun cells were fixed and stained with DAPI. b The level of NPM1-mA in leukemia cells were measured by western blot analysis.

Additional file 5 : Table S5. The top 10 proteins with specific binding to HOTAIRM1 identified by mass spectrometry analysis.

Additional file 7 : Figure S2. The expression levels of HOTAIRM1 in the nucleus and cytoplasm of leukemia cells were measured by qRT-PCR.

Additional file 20 : Figure S15. Cytoplasmic HOTAIRM1 promotes cell cycle progression and inhibits apoptosis in leukemia cells through ULK3. a-b Flow cytometry was used to analyze the changes in cell the cycle (a) and apoptosis (b) in HOTAIRM1-silenced OCI-AML3 cells following ULK3 upregulation. c-d Flow cytometry was used to analyze the change in the cell cycle (c) and apoptosis (d) in HOTAIRM1-overexpressed OCI-AML2 cells following ULK3 downregulation. The data are presented as the mean ± SD of three independent experiments. *P

Additional file 8 : Figure S3. NPM1-mA expression in leukemia cells in the different treatment groups. a The efficiency of RNA interference-mediated knockdown of NPM1-mA expression was determined by qRT-PCR. b The efficiency of RNA interference-mediated knockdown of NPM1-mA expression was determined by western blotting. c NPM1-mA protein levels in NPM1-mA enforced OCI-AML2 cells. d Western blot analysis of NPM1-mA in OCI-AML3 cells treated with KPT-330. β-tubulin as the cytoplasmic control and PCNA as the nuclear control. The data are presented as the mean ± SD of three independent experiments.

4H-SiC power DMOSFETs with breakdown voltage higher than 8.0 kV has been successfully fabricated by using an 60μm-thick, 1.0×1015 cm−3 doped drift epilayer. In this paper, the simulation, the fabrication, and the electrical characteristics of 4H-SiC DMOSFETs were reported. A peak effective channel mobility of 20 cm2/Vs was extracted from a test MOSFET. A specific on-resistance of 80 mΩ-cm2 were measured with at a V GS of 20V, a 32% reduction in R on sp , compared to a previously reported value. A leakage current of 12 μΑ was measured at a drain bias of 8.0 kV from a 4H-SiC DMOSFE with an active area of 1.0×10−2 cm2. In this report, four new termination structures (T1-T3) were implemented in test PiN diodes and tested, for a reduction of termination length.

A silicon carbide (SiC) vertical channel junction field effect transistor (VJFET) was fabricated based on in-house SiC epitaxial wafer with trenched and implanted method. Its forward drain current is in excess of 3.12 A (170 W/cm2) with a current gain of ID/IG = 19746 at gate bias VG = 3 V and drain bias VD = 5.5 V. The SiC VJFET device’s related specific on-resistance 54 mΩ·cm2. The BV gain is 250 V with Vg from -10 V to -4 V and is 350 V with Vg from -4 V to -2 V. Self-aligned floating guard rings provide edge termination that blocks 3180V at a gate bias of ?14 V and a drain-current density of 1.53 mA/cm2.

A 4H-SiC MOSFET with breakdown voltage higher than 1200V has been successfully designed and fabricated. Numerical simulations have been performed to optimize the parameters of DMOSFET. The n-type epilayer is 10 μm thick with a doping of 6×1015 cm−3. The devices were fabricated with a floating guard ring edge termination. The drain current Id = 10 A at Vg = 20 V, corresponding to Vd = 2.0 V.

In this work, the degradation mechanism of 1.2kV 4H-SiC MOSFET under repetitive Unclamped Inductive Switching (UIS) stress has been investigated. The hot-holes injection and trapping into the gate oxide above the JFET region is observed, resulting in the increase of the off-state drain-source leakage current (I DSS ) and the decrease of the on-state resistance (R dson ). Moreover, an improved device with step gate oxide above the JFET region is proposed, which can effectively restrict the degradation under repetitive UIS stress, while the fresh breakdown voltage (BV) and R dson are almost unaffected.

Results are presented for the silicon carbide (SiC) vertical channel junction field effect transistor (VJFET) fabricated based on in-house SiC epitaxial wafer suitable for power devices. The Normally-off 1300V SiC VJFET device's current density is 260 A/cm 2 and current is 8 A at VG= 7 V and VD = 2 V, with related specific on-resistance 7.56 mΩ·cm 2 . The device exceeds 1300 V at gate bias VG = 0 V.

The design, fabrication, and electrical characteristics of a 4H-SiC PiN diode with breakdown voltage higher than 17 kV are presented. The three-zone JTE has been used in the fabrication. Numerical simulations have been performed to optimize the parameters of the edge termination technique. The epilayer properties of the N-type are 175 μm with a doping of 2 × 1014 cm−3. With the three-zone JTE, a typical breakdown voltage of 17 kV has been achieved.

The design, fabrication, and electrical characteristics of the 4H-SiC JBS diode with a breakdown voltage higher than 10 kV are presented. 60 floating guard rings have been used in the fabrication. Numerical simulations have been performed to select the doping level and thickness of the drift layer and the effectiveness of the edge termination technique. The n-type epilayer is 100 μm in thickness with a doping of 6 × 1014 cm−3. The on-state voltage was 2.7 V at JF = 13 A/cm2.