Identification of a t(X;17)(q28;q21) generating a KANSL1-MTCP1 gene fusion leading to dysregulated expression of MTCP1 in acute myeloid leukemia.

Chromosomal translocations and generating fusion genes are closely associated with disease initiation and progression in acute myeloid leukemia (AML). In this study, we identified a novel t(X;17)(q28;q21) chromosomal rearrangement in a patient with acute monocytic leukemia. Using RNA-sequencing, we identified a KANSL1-MTCP1 and a KANSL1-CMC4 fusion gene. 5'-UTR sequences of the KANSL1 gene were found to become fused upstream of the coding sequence region of the MTCP1 and CMC4 genes, respectively, resulting in an aberrantly high expression of these genes. Functional studies revealed that overexpression of the MTCP1 gene induced an increased cell proliferation and partial blockage of cell differentiation, suggesting that the aberrant expression of MTCP1 is of critical importance in leukemogenesis.

Homoharringtonine deregulates MYC transcriptional expression by directly binding NF-κB repressing factor.

Homoharringtonine (HHT), a known protein synthesis inhibitor, has an anti-myeloid leukemia effect and potentiates the therapeutic efficacy of anthracycline/cytarabine induction regimens for acute myelogenous leukemia (AML) with favorable and intermediate prognoses, especially in the t(8;21) subtype. Here we provide evidence showing that HHT inhibits the activity of leukemia-initiating cells (Lin-/Sca-1-/c-kit+; LICs) in a t(8;21) murine leukemia model and exerts a down-regulating effect on MYC pathway genes in human t(8;21) leukemia cells (Kasumi-1). We discovered that NF-κB repressing factor (NKRF) is bound directly by HHT via the second double-strand RNA-binding motif (DSRM2) domain, which is the nuclear localization signal of NKRF. A series of deletion and mutagenesis experiments mapped HHT direct binding sites to K479 and C480 amino acids in the DSRM2 domain. HHT treatment shifts NKRF from the nucleus (including nucleoli) to the cytoplasm by occupying the DSRM2 domain, strengthens the p65-NKRF interaction, and interferes with p65-p50 complex formation, thereby attenuating the transactivation activity of p65 on the MYC gene. Moreover, HHT significantly decreases the expression of KIT, a frequently mutated and/or highly expressed gene in t(8;21) AML, in concert with MYC down-regulation. Our work thus identifies a mechanism of action of HHT that is different from, but acts in concert with, the known mode of action of this compound. These results justify further clinical testing of HHT in AML.

[Prognosis of patients with intracerebral hemorrhage].

OBJECTIVE: To study the related factors of patients with intracerebral hemorrhage (ICH) so as to guide treatment and predict prognosis. METHODS: The prognostic factors of 463 cases with intracerebral hemorrhage were analyzed with single factor and Logistic regression analyses. RESULTS: Age, Glasgow coma scale, amount of hemorrhage, NIHSS score, mean arterial blood pressure, with or without ventricular breakage, with or without midline shift and the incidence of complications at random blood glucose levels were analyzed for the correlation with the prognosis of patients. The poor prognosis group had significant differences with the good prognosis group with regards to these factors. The average age of patients with a poor prognosis was 71 years old, the average hematoma volume 29 ml and the average GCS score 11.2 versus 65 years old, 15 ml, 15.1 for those with a good prognosis (P < 0.05). Logistic regression analysis showed that age, amount of hemorrhage and disturbance of consciousness was an independent adverse prognostic factor for cerebral hemorrhage at three months. The OR values were 1.32, 8.66 and 1.08 respectively. CONCLUSION: The etiologies of ICH are diverse. Maintaining normal blood pressure is an important preventive measure for ICH. Hematoma volume, disturbance of consciousness and age may be used to predict the prognosis of cerebral hemorrhage.