SET-CAN/NUP214
fusion is a recurrent event commonly observed in adult male patients diagnosed with T-cell acute lymphoblastic leukemia (T-ALL) and has occasionally been reported in other diseases ...such as acute myeloid leukemia (AML), myeloid sarcoma (MS), acute undifferentiated leukemia (AUL), chronic myeloid leukemia (CML) and B-cell acute lymphoblastic leukemia (B-ALL). This fusion gene is derived from chromosome del(9)(q34.11;q34.13) or t(9;9)(q34;q34) and may have an inhibitory effect on primitive progenitor differentiation. The prognosis of the reported patients is varied, with these patients often show resistance to chemotherapy regimens that include high doses of glucocorticoids. The optional treatment has not been determined, more cases need to be accumulated and evaluated. The scope of this review is to summarize the general features and prognostic significance in leukemia associated with the
SET-CAN/NUP214
fusion gene and to discuss the methods of detection and treatment, aiming at providing some useful references for relevant researchers in the field of blood tumor.
Genomic loss of mismatched human leukocyte antigen (HLA loss) is one of the most vital immune escape mechanisms of leukemic cells after allogeneic hematopoietic stem cell transplantation (allo-HSCT). ...However, the methods currently used for HLA loss analysis have some shortcomings. Limited literature has been published, especially in lymphoid malignancies. This study aims to evaluate the incidences, risk factors of HLA loss, and clinical outcomes of HLA loss patients. In all, 160 patients undergoing partially mismatched related donor (MMRD) transplantation from 18 centers in China were selected for HLA loss analysis with the next-generation sequencing (NGS)-based method, which was validated by HLA-KMR. Variables of the prognostic risk factors for HLA loss or HLA loss–related relapse were identified with the logistic regression or the Fine and Gray regression model. An HLA loss detection system, HLA-CLN HLA chimerism for loss of heterozygosity (LOH) analysis by NGS, was successfully developed. Forty (25.0%) patients with HLA loss were reported, including 27 with myeloid and 13 with lymphoid malignancies. Surprisingly, 6 of those 40 patients did not relapse. The 2-year cumulative incidences of HLA loss (22.7% vs 22.0%, P = 0.731) and HLA loss–related relapse (18.4% vs 20.0%, P = 0.616) were similar between patients with myeloid and lymphoid malignancies. The number of HLA mismatches (5/10 vs <5/10) was significantly associated with HLA loss in the whole cohort odds ratio (OR): 3.15, P = 0.021 and patients with myeloid malignancies (OR: 3.94, P = 0.021). A higher refined-disease risk index (OR: 6.91, P = 0.033) and donor–recipient ABO incompatibility (OR: 4.58, P = 0.057) contributed to HLA loss in lymphoid malignancies. To sum up, HLA-CLN could overcome the limitations of HLA-KMR and achieve a better HLA coverage for more patients. The clinical characteristics and outcomes were similar in patients with HLA loss between myeloid and lymphoid malignancies. In addition, the results suggested that a patient with HLA loss might not always relapse.
Anthracyclines and cytarabine have comprised standard induction therapy for acute myeloid leukemia (AML) for decades. Low overall survival of AML is due to non-remission or relapse after remission. ...Hypomethylating agent (HMA) decitabine combined with low-dose chemotherapy or other targeted agents has shown promising effect for AML in clinical trials, especially in t(8;21) acute myeloid leukemia. We previously investigated histone deacetylase inhibitor (HDACi) chidamide could regulate Wnt/β-catenin signaling pathway in leukemia cell lines.
Adult patients with de novo or relapsed/refractory AML who were treated with chidamide and decitabine in combination with chemotherapy (chidamide group, n = 23) or only decitabine combination with chemotherapy (decitabine group, n = 17) were analyzed.
Chidamide group represented higher complete response rate (82.6% and 52.9%, p = 0.0430, vs. decitabine group), progression-free survival and overall survival rates (p = 0.0088 and p = 0.0139, respectively), especially for patients with de novo AML. Hematological toxicity and infections were the most common adverse events (AEs) in both groups, and they were manageable by supportive treatments.
This HDACi- and HMA-based protocol is an effective and tolerable therapy for patients with AML. The comprehensive mechanism and effects of chidamide in combination with decitabine are worth to be further explored in AML.
The aim of this study was to determine the efficacy and safety of treatment of pediatric acute promyelocytic leukemia (APL) with single-agent arsenic trioxide (ATO). A total of 19 children (≤ 15 ...years of age) with newly diagnosed APL were treated with single-agent ATO for remission induction and postremission therapy. Seventeen of the children (89.5%) achieved complete hematologic remission, and 2 early deaths occurred from intracranial hemorrhage. ATO-induced leukocytosis was observed in 13 (68.4%) patients. Other ATO-related toxicities were minimal and transient. Postremission ATO therapy continued for 3 years; the most common side effect was ATO-induced neutropenia. With a median follow-up of 53 months (range, 23-76 months), the calculated 5-year overall survival and event-free survival were 83.9% and 72.7%, respectively, which are comparable with results achieved by the use of ATRA plus chemotherapy, which is the standard therapy for APL. No chronic arsenic toxicity or second malignancies were found during the follow-up period, and arsenic retention was not significant in patients off treatment more than 24 months. ATO resistance was observed in only 1 patient with a complex karyotype. The results indicate the high efficacy and safety of single-agent ATO regimens in the treatment of children with de novo APL.
The aim of the present study was to investigate the effects of rapamycin and its underlying mechanisms on acute lymphoblastic leukemia (ALL) cells. We found that the p14, p15, and p57 genes were not ...expressed in ALL cell lines (Molt-4 and Nalm-6) and adult ALL patients, whereas mTOR, 4E-BP1, and p70S6K were highly expressed. In Molt-4 and Nalm-6 cells exposed to rapamycin, cell viability decreased and the cell cycle was arrested at the G1/S phase. Rapamycin restored p14, p15, and p57 gene expression through demethylation of the promoters of these genes. As expected, rapamycin also increased p14 and p15 protein expression in both Molt-4 and Nalm-6 cells, as well as p57 protein expression in Nalm-6 cells. Rapamycin additionally decreased mTOR and p70S6K mRNA levels, as well as p70S6K and p-p70S6K protein levels. However, depletion of mTOR by siRNA did not alter the expression and promoter methylation states of p14, p15, and p57. These results indicate that the inhibitory effect of rapamycin may be due mainly to increased p14, p15, and p57 expression via promoter demethylation and decreased mTOR and p70S6K expression in ALL cell lines. These results suggest a potential role for rapamycin in the treatment of adult ALL.
Administration of various chemotherapeutic agents is associated with an increased risk of thrombotic events. Although vascular endothelium plays a predominant role in blood coagulation and ...fibrinolysis, the effect of cytotoxic drugs on the procoagulant activity (PCA) of endothelial cells has not been well evaluated. Our study aims to investigate the possibility that daunorubicin, a chemotherapeutic agent, exerts prothrombotic effect on endothelial cells. We tested the impact of daunorubicin on phosphatidylserine (PS) exposure, endothelial microparticles (EMPs) release and consequent PCA. Human umbilical vein endothelial cells (HUVECs) were treated with daunorubicin (0.1, 0.2, 0.5, 1, 2 mM) for 24 hours. PCA of HUVECs was measured using clotting time and purified coagulation complex assays. Counts and PCA of EMPs were evaluated by flow cytometry and clotting time assay, respectively. Lactadherin was used as a novel probe for detection of PS exposure and EMPs release. We found that daunorubicin dose-dependently increased the PS exposure and consequent PCA of HUVECs. Moreover, daunorubicin treatment also enhanced the release of EMPs which were highly procoagulant. This increment was especially significant at 0.2 mM of daunorubicin or more. Blockade of PS with lactadherin inhibited over 90% of HUVECs and EMPs PCA. However, anti-TF antibody had no significant inhibition effect. Our results demonstrate that daunorubicin treatment enhanced PCA of HUVECs through PS exposure and shedding of procoagulant EMPs. Lactadherin acts as an efficient anticoagulant in this process.
Hematopoietic stem cell transplantation (HSCT) has benefited an increasing number of patients with hematological disease in the clinic. It is a curative therapy for malignant and nonmalignant ...hematological diseases. With the advancement and further clinical application of HSCT in recent years, the life expectancy of patients has increased, but complications have become more common. The occurrence of ocular complications is receiving increasing attention because they can seriously affect the quality of life of patients. Ocular complications require increased attention from clinicians because of their negative impact on patients and increasing incidence. Most of recent reports on posttransplant ocular complications involve ocular manifestations of graft-versus-host disease (GVHD), and a few ocular complications that do not originate from GVHD have also been reported. This review summarizes the diagnosis, scoring criteria, pathophysiology, and clinical manifestations of and common therapies for ocular graft-versus-host disease(oGVHD) after HSCT, and includes a description of some rare cases and novel therapies.
Arsenic speciation in cerebrospinal fluid (CSF) is critical for treatment/prevention of central nervous system (CNS) relapse in acute promyelocytic leukaemia (APL) patients treated with arsenic ...trioxide (ATO). Previous study showed low total arsenic level in CSF of APL patients. Mannitol infusion was applied to improve blood–brain barrier (BBB) permeability for arsenic. Arsenite (AsIII), monomethylarsonic acid (MMAV), dimethylarsinic acid (DMAV), and arsenate (AsV) in CSF and plasma were analysed by high performance liquid chromatography‐hydride generation‐atomic fluorescence spectrometry (HPLC‐HG‐AFS). The profile and concentration of arsenic species in CSF from APL patients administered ATO alone and in combination with mannitol were compared. The overall distribution trend of arsenic species in CSF was AsIII, DMAV > MMAV > AsV. Arsenicals accumulated in CSF with administration frequency. The permeability of BBB for AsIII was higher than that for MMAV and DMAV. Arsenic concentration in CSF was much lower than that in plasma. There were significantly higher arsenic species concentrations in CSF of APL patients treated with mannitol than that without mannitol. Mannitol infusion significantly increased AsIII penetration into CSF, which was beneficial to optimize efficacy in APL patients with CNS relapse.
