Effect of obesity on the efficacy of allogeneic hematopoietic stem cell transplantation / 白血病·淋巴瘤

Objective:To investigate the effect of obesity on the efficacy of allogeneic hematopoietic stem cell transplantation.Methods:The clinical data of 81 patients who underwent allogeneic hematopoietic stem cell transplantation from August 2017 to September 2020 in the First Affiliated Hospital of Nanjing Medical University were retrospectively analyzed. According to the body mass index (BMI), the patients were divided into the obese group (BMI≥28 kg/m 2, 11 cases) and the non-obese group (BMI<28 kg/m 2, 70 cases). The clinicopathological characteristics, hematopoietic stem cell implantation, post-transplantation complications, survival and recurrence were compared between the two groups. Univariate and multivariate survival analyses were performed by using Cox proportional hazards regression model. Results:The median follow-up time of 81 patients was 280 d (8-1 218 d). The 1-year overall survival (OS) rate was 77.9%, and the 1-year progression-free survival (PFS) rate was 73.8%. The 1-year OS rates of the non-obese group and the obese group were 82.6% and 46.2% ( χ2 = 15.54, P<0.01), and the 1-year PFS rates were 82.1% and 36.4% ( χ2 = 15.56, P<0.01). The non-recurrence mortality (NRM) rates of the non-obese group and the obese group were 7.1% and 32.7% ( χ2 = 6.463, P = 0.01), and the cumulative recurrence rate was 11.5% and 42.9% ( χ2 = 8.146, P = 0.004). Between the non-obese group and the obese group, the median engraft time of neutrophils and platelets, acute graft-versus-host disease, chronic graft-versus-host disease, hemorrhagic cystitis, cytomegalovirus infection and Epstein-Barr virus infection had no statistical difference ( P > 0.05). The result of multivariate analysis showed that obesity was an independent adverse influencing factor for OS of patients with allogeneic hematopoietic stem cell transplantation ( HR = 3.814, 95% CI 1.343-10.827, P = 0.012). Conclusion:Obesity is an important unfavorable factor that affects patient's survival after allogeneic hematopoietic stem cell transplantation, and the improvement of the efficacy and survival of these patients is worthy of further study.

Analysis of prognosis of acute myeloid leukemia patients based on genetic mutations / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To correlate the clinical features of patients with acute myeloid leukemia (AML) with mutations of FLT3-ITD, NPM1, CEBPA, c-KIT, DNMT3A and ND4 genes as well as chromosomal aberrations.</p><p><b>METHODS</b>Somatic mutations of aforementioned genes in 412 newly diagnosed AML patients were detected with PCR and direct sequencing. All patients were also subjected to R-banding chromosomal analysis. The results were correlated with the clinical features and prognosis of the patients.</p><p><b>RESULTS</b>The mutation rates of FLT3-ITD, NPM1, CEBPA, c-KIT, DNMT3A and ND4 were 9.0% (26/289), 19.1% (50/262), 18.9% (34/180), 3.4% (7/208), 6.6% (9/137) and 6.9% (4/58), respectively. Patients with poor prognosis based on genetic mutations had lower blood platelet count than those with intermediate and good prognosis (P=0.001 and P=0.001, respectively). None of the three groups attained median overall survival (OS) (P> 0.05). The complete remission (CR) was similar among the three groups (P> 0.05). For patients with different prognosis based on cytogenetic findings, white blood cell count in those with intermediate prognosis was higher than those with good and poor prognosis (P< 0.001 and P=0.004, respectively), while the blood platelet count of the intermediate group was higher than that of the group with good prognosis (P=0.018). No significant difference was found among the three groups in terms of hemoglobin level (P> 0.05). The group with poor prognosis has attained shorter OS compared with those with good and intermediate prognosis (P< 0.001 and P=0.003, respectively). However, the CR rate of the group with good prognosis was higher than that of the intermediate group (P=0.001). For the group with intermediate prognosis, presence of genetic mutations did not correlate with the clinic characteristics such as white blood cell count, blood platelet count, hemoglobin level, OS and CR rate (P> 0.05 for all comparisons).</p><p><b>CONCLUSION</b>Genetic mutations combined with cytogenetic analysis can facilitate the prognosis and personalized treatment for patients with AML.</p>

Treatment progress of elderly acute myeloid leukemia:reports from the 57th American Society of Hematology annual meeting / 白血病·淋巴瘤

Elderly acute myeloid leukemia (AML) accounted for 35 % of all AML with the increased incidence year by year, and the median onset age is 67 years old. Generally, AML patients require strong chemotherapy, but older patients often cannot tolerate intense chemotherapy due to the viscera dysfunction. It is still lack of unified treatment clinically. Reports on treatment of elderly AML in the 57th American Society of Hematology (ASH) annual meeting covered multiple fields, in which the traditional induction chemotherapy, demethylation drug alone or in combination with other drugs, and novel drugs were an involved. This article reviewed the latest research on the elderly AML in the 57th ASH annual meeting.

Matrine suppresses the growth of human chronic myeloid leukemia K562 cells via inhibiting bcr-abl-mediated MEK-ERK pathway / 肿瘤研究与临床

Objective To investigate the mechanism of matrine in inhibition of proliferation the proliferation of human chronic myeloid leukemia (CML) K562 cells via MEK-ERK signaling pathway. Methods Western blot was used to detect the expression of MEK1, ERK1/2, Shc and SHP2 (the signal effect molecules of MEK-ERK pathway) in K562 cells. The transcription and translation of bcr-abl and target protein (bcl-xL, Cyclin D1, c-myc and p27) were detected by RT-PCR and Western blot. Results Matrine was able to significantly inhibit the phosphorylation of MEK1, ERK1/2, Shc and SHP2 in K562 cells and suppress the protein and mRNA expression of bcr-abl. Moreover, the expressions of bcl-xL, Cyclin D1 and c-myc were down-regulated significantly, while the expression level of p27 (a negative regulator of cell cycle progression) was increased markedly after matrine treatment. Conclusions Suppression of the growth of human CML K562 cells is related to the inhibition of bcr-abl-mediated MEK-ERK pathway activity. The down-regulation of phosphorylated proteins or protein kinases activity in signaling pathways might be an important molecular mechanism in control the activity of MEK-ERK pathway.

Growth inhibition effect of matrine on K562 cells mediated by IL-6/JAK/STAT3 signaling pathway / 中华血液学杂志

<p><b>OBJECTIVE</b>To investigate the molecular mechanism of the growth inhibitory effect of matrine on K562 cells in JAK/STAT3 mediated signal pathway.</p><p><b>METHODS</b>Western blot analyses were performed to investigate the differential expression of JAK2, STAT3, phosphor-STAT3 (Tyr705 & Ser727) and phosphor-JAK2 proteins after matrine treatment in K562 cells with or without human recombinant interleukin 6 (IL-6) pretreatment. The expression of STAT3 response gene products such as Bcl-xL, Cyclin D1 and c-Myc, were investigated by Western blot and quantitative real time RT-PCR (qRT-PCR). Expression of IL-6, a potent upstream activating factor of JAK/STAT3 pathway, was analyzed by both real time qRT-PCR and ELISA.</p><p><b>RESUTLS</b>Western blot revealed that matrine treatment resulted in a strong down-regulation of phosphor-STAT3 both in Tyr705 and Ser727 sites or phosphor-JAK2 proteins expression without significant effects on the total STAT3 and JAK2 proteins. The expression of phosphor-Tyr705 STAT3 and phosphor-Ser727 STAT3 was decreased to 0.370 ± 0.172 in K562 cells treated with 0.5 mg/ml matrine for 48 h, respectively, from 0.690 ± 0.119 and 1.150 ± 0.263 in control cells, accompanied with a dramatical down-regulation of phosphor-JAK2 from 0.670 ± 0.137 to 0.049 ± 0.057 (P<0.05). In addition, it was found that the expression of Bcl-xL, Cyclin D1, c-Myc was decreased both at the transcription and protein level in K562 cells after matrine treatment. Matrine treatment resulted in a significant decrease in the expression level of IL-6 in K562 cells from (35.1 ± 1.93) to (10.74 ± 1.83) and (8.66 ± 1.24) pg/ml at the dose of 0.5 and 0.8 mg/ml, respectively (p<0.05). Matrine treatment could diminish the up-regulation of STAT3, JAK2, phosphor-STAT3 and phosphor-JAK2 protein following pretreatment with IL-6 in K562 cells.</p><p><b>CONCLUSION</b>Matrine exerts its anti-leukemia effect by interfering with the JAK2/STAT3 signaling pathway. The inhibition of IL-6 expression may play a pivotal role in the disruption of JAK/STAT pathway by matrine.</p>

Analysis of ND4 gene mutations in acute myelogenous leukemia / 中华血液学杂志

<p><b>OBJECTIVE</b>To investigate the relationship of the mutational status of the ND4 gene and the clinical features of acute myelogenous leukemia (AML) patients with ND4 mutations.</p><p><b>METHODS</b>Using PCR combined with directly sequencing, we identified somatic mutations of ND4 in 121 primary AML patients to couple with their clinical features.</p><p><b>RESULTS</b>There were 58 male patients and 63 female patients (median age 49 years, 10-86 years). Eight of 121 patients (6.6%) with de novo AML were found harboring missense mutation of ND4 gene, including 3 patients with A131V (3/8, 37.5%), 2 patients with A404T (2/8, 25%), 1 patient with F149L (1/8, 12.5%), 1 patient with G242D (1/8, 12.5%) and 1 patient with Y409H (1/8, 12.5%), respectively. Patients with ND4 mutations were associated with good karyotype (P=0.049), regardless of gender, age, white blood cell, hemoglobin, platelet, blast cells of bone marrow or immunophenotype (P>0.05). There were no statistical significance in mutations of FLT3-ITD, NPM1, CEBPA, c-KIT and DNMT3A between patients with ND4 mutation and wild-type (wt) ND4 (P>0.05). The median overall survival of patients with ND4 mutations and wt ND4 were all not reached. The median relapse-free survival were not reached and 29(2-53) months, respectively (P>0.05). There was no significance in the ratio of CR and RR patients between wt ND4 and ND4 mutated groups (P>0.05).</p><p><b>CONCLUSION</b>It was concluded that novel ND4 mutations could be found in de novo AML patients, especially in patients with good karyotype. Thus, ND4 mutations might play an important role in AML prognosis. However, whether the mitochondria dysfunction contribute to leukemogenesis needs to be further investigated.</p>

Up-regulation of NKG2D ligand ULBP2 by matrine in K562 cells and the underlying molecular mechanisms / 中华血液学杂志

<p><b>OBJECTIVE</b>To probe matrine acting on natural killer cell (NK) activating receptor NKG2D ligands expression in CML cell line K562 and its underlying molecular mechanism.</p><p><b>METHODS</b>The expression of NKG2D ligands (major histocompatibility complex class I chain-related molecule A or B (MICA/B), UL16-binding proteins (ULBP) 1, 2, and 3 on K562 cells were analyzed before and after treated with matrine by FCM. The cytotoxic sensitivity of K562 to NK cell was detected by FCM after CFSE staining at different effect-to-target (E/T) cell ratios. The expression of signal transduction and transcriptional activator 3 (STAT3) protein as well as phosphorylated STAT3 (p-STAT3) were detected by western blot.</p><p><b>RESULTS</b>After treatment with matrine, ULBP1 and ULBP2 expression, especially ULBP2 on K562 cells significantly increased, with mean fluorescence intensity (MFI) increasing to 615 and 1614 by 220 and 615 in the untreated cells, respectively. There was no significant change for MICA or ULBP3 expression. Matrine enhanced the susceptibility of K562 cells to NK-mediated cell lysis. At the ratio of E/T with 5:1, the proportion of the killed K562 cells increased to 32.8%, 38.1% and 40.5%, respectively (after 0.2, 0.5 and 0.8 mg/ml matrine treatment) by 29.2% in the untreated cells. The phosphorylated STAT3 protein, but not STAT3 protein, was significantly inhibited by matrine treatment in K562 cells.</p><p><b>CONCLUSION</b>Matrine induced the expression of NKG2D ligands in K562cells and enhanced the cytotoxicity of NK cells against K562, which was closely related to the inhibition of STAT3 activity in K562 cell.</p>