Acute myeloid leukemia immune escape by epigenetic CD48 silencing.

Acute myeloid leukemia (AML) is a malignant disorder of hemopoietic stem cells. AML can escape immunosurveillance of natural killer (NK) by gene mutation, fusions and epigenetic modification. The mechanism of AML immune evasion is not clearly understood. Here we show that CD48 high expression is a favorable prognosis factor that is down-regulated in AML patients, which can help AML evade from NK cell recognition and killing. Furthermore, we demonstrate that CD48 expression is regulated by methylation and that a hypomethylating agent can increase the CD48 expression, which increases the NK cells killing in vitro. Finally, we show that CD48 high expression can reverse the AML immune evasion and activate NK cells function in vivo. The present study suggests that a combination the hypomethylating agent and NK cell infusion could be a new strategy to cure AML.

[Pathogens in Bloodstream Infection in Patients with Hematological Diseases: Retrospective Analysis].

OBJECTIVE: To analyze the distribution and drug resistance of pathogens sampled from the patients with bloodstream infection in the department of hematology of PLA General Hospital, so as to provide evidences for clinical prevention and control infection. METHODS: From January 2014 to December 2017, A total of 286 cases-time positive blood culture samples from 212 patients in the department of hematology of the General Hospital of Chinese PLA were collected. The clinical characteristics of patients and the distribution and drug resistance of pathogens were analyzed retrospectively. RESULTS: 182(63.64%) bacterial strains were Gram-negative, and the other 104(36.36%) were Gram-positive. There were 88 strains of Escherichia coli(30.77%), 34 strains of Pseudomonas aeruginosa(11.89%), 26 strains of Klebsiella pneumoniae(9.09%), 25 strains of Staphylococcus epidermidis(8.74%), 20 strains of Gram-positive rods(6.99%), 16 strains of Staphylococcus hominis(5.59%), 11 strains of Etaphylococcus haemolyticus(3.85%), 10 strains of Staphylococcus aureus(3.50%), 6 strains of Staphylococcus capitis(2.10%), 5 strains of Acinetobacter baumannii(1.75%) and so on. Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumoniae as Gram-negative bacteria were sensitive to amikacin. Staphylococcus epidermidis and Staphylococcus aureus as Gram-positive bacteria were sensitive to vancomycin and nitrofurantoin. CONCLUSION: The blood culture patients with bloodstream infection in department of hematology of our hospital confirmed that more infections are Gram-negative. The clinicians should choose suitable antibiotics according to the results of bacterial culture and drug sensitive test.

Profiling of somatic mutations and fusion genes in acute myeloid leukemia patients with FLT3-ITD or FLT3-TKD mutation at diagnosis reveals distinct evolutionary patterns.

BACKGROUND: The receptor tyrosine kinase FLT3 with internal tandem duplications within the juxtamembrane domain (FLT3-ITD) is a poor prognostic factor; however, the prognostic significance of missense mutation in the tyrosine kinase domain (FLT3-TKD) is controversial. Furthermore, the accompanying mutations and fusion genes with FLT3 mutations are unclear in acute myeloid leukemia (AML). METHODS: We investigated FLT3 mutations and their correlation with other gene mutations and gene fusions through two RNA-seq based next-generation sequencing (NGS) method and prognostic impact in 207 de novo AML patients. RESULTS: FLT3-ITD mutations were positive in 58 patients (28%), and FLT3-TKD mutations were positive in 20 patients (9.7%). FLT3-ITD was associated with a higher white blood cell count (WBC, mean 72.9 × 109/L vs. 24.2 × 109/L, P = 0.000), higher bone marrow blasts (mean 65.9% vs. 56.0%, P = 0.024), and NK-AML (normal karyotype) (64.8% vs. 48.4%, P = 0.043). NPM1 and DNMT3A mutations were enriched in FLT3-ITD (53.5% vs. 15.3%, P = 0.000; 34.6% vs. 13%, P = 0.003). However, the mutations of CEBPA were excluded in FLT3-AML (3.8% vs. 0% vs. 19.8%, P = 0.005). Mutations of Ras and TP53 were unlikely associated with FLT3-ITD (1.9% vs. 20.6%, P = 0.006; 0% vs. 6.1%, P = 0.04). The common fusion genes (> 10%) in FLT3-ITD had MLL-rearrangement and NUP98-rearrangement, while the common fusion genes in FLT3-TKD had AML1-ETO and MLL-rearrangement. Two novel fusion genes PRDM16-SKI and EFAN2-ZNF238 were identified in FLT3-ITD patients. Gene fusions and NPM1 mutation were mutually excluded in FLT3-ITD and FLT3-TKD patients. Their patterns of mutual exclusivity and cooperation among mutated genes suggest that additional driver genetic alterations are required and reveal two evolutionary patterns of FLT3 pathogenesis. Patients with FLT3-ITD had a lower CR (complete remission) rate, lower 3-year OS (overall survival), DFS (disease-free survival), and EFS (event-free survival) compared to FLT3wtAML. NK-AML with FLT3-ITD had a lower 3-year OS, DFS, and EFS than those without, while FLT3-TKD did not influence the survival in whole cohort and NK-AML. Besides, we found that FLT3-ITD/TET2 bimutation defined a poor prognostic subgroup. CONCLUSIONS: Our study offers deep insights into the molecular pathogenesis and biology of AML with FLT3-ITD and FLT3-TKD by providing the profiles of concurrent molecular alterations and the clinical impact of FLT3-ITD and FLT3-TKD on AML patients.

Chidamide in combination with chemotherapy in refractory and relapsed T lymphoblastic lymphoma/leukemia.

Chidamide, a novel histone deacetylase inhibitor, has exerted effects in T-cell tumors through various mechanisms. Seventeen patients with refractory or relapsed T-cell acute lymphoblastic lymphoma/leukemia (T-LBL/ALL) received Chidamide combined with chemotherapy as salvage treatment. Historical data was analyzed as comparison as chemotherapy group. Complete response (CR) rate and overall response rate (ORR) of Chidamide + chemotherapy group were higher than that of chemotherapy group after one course. Chidamide + chemotherapy group had a better progress-free survival (PFS) compared to chemotherapy group. No difference in overall survival (OS) was observed. Grade 3/4 nonhematological adverse events (>10%) of patients in Chidamide + chemotherapy group included febrile neutropenia (64.7%), drug-induced liver failure (17.6%), decreased fibrinogen (11.8%), sepsis (11.8%), pneumonitis (11.8%), and oral mucositis (11.8%). This study demonstrates that Chidamide included regimen may be a new treatment strategy with an acceptable safety profile for refractory or relapsed T-LBL/ALL patients but requires further investigation.

[Diagnostic Values of Procalcitonin, C-reactive Protein and Interleukin-6 in Hematological Diseases with Bacterial Infection].

OBJECTIVE: To evaluate the diagnostic values of procalcitonin(PCT), C-reactive protein(CRP) and interleukin-6 (IL-6) in patients suffered from hematological diseases with bacterial infection, and to provide further evidence for clinical application. METHODS: A total of 3631 blood cultures, serum levels of PCT and CRP and IL-6 (n=1587) from the inpatients from 2014-01-02 to 2018-01-27 were retrospectively analyzed. The patients were divided into positive (n=208) and negative blood culture (n=3423) groups. Positive blood culture group were redivided into gram-positive (n=34) and gram-negative (n=174) subgroups. The values CRP, PCT and IL-6 were compared respectively in these groups. The data were analyzed by using R 3.4.4 language. RESULTS: The medians of PCT values in positive and negative blood culture groups were 0.41(0.04-103.34) µg/L and 0.20(0.02-200) µg/L(P<0.001) respectively. The medians of CRP values in positive and negative blood culture groups were 9.49(0.1-370) mg/dl and 5.42(0-370) mg/dl (P<0.001) respectively. The medians of IL-6 values in positive and negative blood culture groups were 186.1(2.0-5000, n=91) pg/ml and 52.65(1.5-5000, n=1496) pg/ml (P<0.001). The medians of PCT values in gram-positive and gram-negative groups were 0.20(0.05-93.83) µg/L and 0.58(0.04-103.34) µg/L (P=0.006) respectively. The medians of CRP value in gram-positive and gram-negative groups were 9.19(0.1-35.3)mg/dL and 9.49(0.1-370) mg/dl (P=0.300) respectively. The medians of IL-6 values in gram-positive and gram-negative groups were 83.01(5.61-1500, n=12) pg/ml and 208(2.0-5000, n=79) pg/ml (P=0.357). CONCLUSION: The PCT, CRP and IL-6 levels were significantly higher in the positive blood culture group than those in the negative blood culture group, so provide the effective early diagnostic markers for blood culture. PCT levels in gram-positive group were significantly higher than that in gram-negative groups, contributing to distinguish between the 2 groups.