The fat mass and obesity-associated protein (FTO) is an RNA demethylase required for catalytic demethylation of N ⁶-methyladenosine (m⁶A); it is highly expressed and functions as an oncogene in acute myeloid leukemia (AML). Currently, the overarching objective of targeting FTO is to precisely inhibit the catalytic activity. Meanwhile, whether FTO degradation also exerts antileukemic effects remains unknown. Herein, we designed the first FTO-targeting proteolysis targeting chimera (PROTAC) degrader QP73 using our FTO inhibitor Dac85-which potently inhibits FTO demethylation in AML cell lines-as a warhead. Notably, QP73 significantly induced FTO degradation in a time-, dose-, and ubiquitin-proteasome system-dependent manner and had superior antiproliferative activities to the FTO inhibitor Dac85 in various AML cell lines. Moreover, QP73 treatment significantly increased m⁶A modification on mRNA, promoted myeloid differentiation, and induced apoptosis of AML cells. Quantitative proteomics analysis showed that QP73 induced complete FTO degradation, upregulating RARA and ASB2 abundance and downregulating CEBPA, MYC, PFKP, and LDHB levels in AML cells. Lastly, QP73 exhibited antileukemic activity by increasing m⁶A modification and decreasing FTO levels in xenograft AML tumors. This proof-of-concept study shows that FTO-targeting PROTAC degraders can regulate the FTO signaling pathway and have potential antileukemia applications.

Objective:To observe the natural course of cerebral contusion and laceration combined with hematoma formation and analyze the risk factors for its progression.Methods:Patients with cerebral contusion and laceration combined with hematoma formation admitted to our hospital from September 2017 to March 2020 were prospectively selected; and they were divided into progressive and non-progressive groups according to progression of cerebral contusion and laceration combined with hematoma formation. The clinical data of the two groups of patients were compared, and multivariate Logistic regression was used to analyze the independent influencing factors for progressive cerebral contusion and laceration combined with hematoma formation.Results:A total of 197 patients with cerebral contusion and laceration combined with hematoma formation were included in this study, of which, 61 were treated with craniotomy and 136 were treated conservatively; 85 patients had progressive cerebral contusion and laceration combined with hematoma formation and 112 patients had non-progressive cerebral contusion and laceration combined with hematoma formation. As compared with those in the non-progressive group, the baseline Glasgow Coma Scale (GCS) scores of the progressive group were lower, hematoma volume by second CT scan was larger, distance from the center of cerebral contusion and laceration or hematoma to the nearest cortex was shorter, platelet count and thrombin time increased, fibrinogen (FIB) content decreased, and proportion of patients with multiple lesions in the first CT scan was higher in the progressive group, with significant differences ( P<0.05). Multivariate Logistic regression analysis showed that the distance from the center of cerebral contusion and laceration or hematoma to the nearest cortex<1 cm, plasma FIB<2 g/L, multiple lesions of cerebral contusion and laceration or hematoma on first CT scan were risk factors for progression in patients with cerebral contusion and laceration combined with hematoma formation ( OR=6.654, 95%CI: 1.391-35.089, P=0.025; OR=5.617, 95%CI: 1.136-28.022, P=0.034; OR=4.629, 95%CI: 1.178-20.071, P=0.031). Conclusion:The patients with short distance from the center of cerebral contusion and laceration or hematoma to the nearest cortex, low plasma FIB, and multiple lesions of cerebral contusion and laceration or hematoma on first CT scan are prone to have progressive cerebral contusion and hematoma formation.