Venetoclax plus a hypomethylating agent versus cytarabine, aclarubicin, and granulocyte colony-stimulating factor chemotherapy as a first-line therapy for newly diagnosed acute myeloid leukemia: A propensity score-matched analysis.

BACKGROUND: Both venetoclax plus a hypomethylating agent (VEN/HMA) and cytarabine, aclarubicin, and granulocyte colony-stimulating factor (CAG) are low-intensity regimens for older patients with acute myeloid leukemia (AML) that show good efficacy and safety. It is unknown how VEN/HMA compares with the CAG regimen for the treatment of newly diagnosed AML. METHODS: The outcomes of patients with newly diagnosed AML treated with VEN/HMA were compared with those of patients treated with a CAG-based regimen. Propensity score matching between these two cohorts at a 1:1 ratio was performed according to age at diagnosis, sex, Eastern Cooperative Oncology Group performance status, state of fitness, and European LeukemiaNet (ELN) 2022 risk stratification to minimize bias. RESULTS: A total of 84 of 96 patients in the VEN/HMA cohort were matched with 84 of 147 patients in the CAG cohort. VEN/HMA resulted in a better response than the CAG-based regimens, as indicated by a higher composite complete remission (CRc) rate (82.1% vs. 60.7%; p = .002) and minimal residual disease negativity rate (88.2% vs. 68.2%; p = .009). In patients with an ELN adverse risk, VEN/HMA was associated with a higher CRc rate compared to CAG (80.5% vs. 58.3%; p = .006). VEN/HMA was associated with longer event-free survival (EFS) (median EFS, not reached vs. 4.5 months; p = .0004), whereas overall survival (OS) was comparable between the two cohorts (median OS, not reached vs. 18 months; p = .078). CONCLUSIONS: The VEN/HMA regimen may result in a better response than CAG-based treatment in older patients with newly diagnosed AML.

The m6A reader IGF2BP2 regulates glutamine metabolism and represents a therapeutic target in acute myeloid leukemia.

N6-Methyladenosine (m6A) modification and its modulators play critical roles and show promise as therapeutic targets in human cancers, including acute myeloid leukemia (AML). IGF2BP2 was recently reported as an m6A binding protein that enhances mRNA stability and translation. However, its function in AML remains largely elusive. Here we report the oncogenic role and the therapeutic targeting of IGF2BP2 in AML. High expression of IGF2BP2 is observed in AML and associates with unfavorable prognosis. IGF2BP2 promotes AML development and self-renewal of leukemia stem/initiation cells by regulating expression of critical targets (e.g., MYC, GPT2, and SLC1A5) in the glutamine metabolism pathways in an m6A-dependent manner. Inhibiting IGF2BP2 with our recently identified small-molecule compound (CWI1-2) shows promising anti-leukemia effects in vitro and in vivo. Collectively, our results reveal a role of IGF2BP2 and m6A modification in amino acid metabolism and highlight the potential of targeting IGF2BP2 as a promising therapeutic strategy in AML.

Turner syndrome with primary myelofibrosis, cirrhosis and ovarian cystic mass: A case report.

BACKGROUND: Turner syndrome (TS) with leukemia is a complicated clinical condition. The clinical course and outcome of these patients are poor, so the treatment and prognosis of TS with hematological malignancies deserve our attention. CASE SUMMARY: Here, we report a case of a 20-year-old woman diagnosed with TS, primary myelofibrosis (PMF), cirrhosis, and an ovarian cystic mass. This is the first report on the coexistence of TS and PMF with the MPL and SH2B3 mutations. The patient was diagnosed with cirrhosis of unknown cause, splenomegaly and severe gastroesophageal varices. Additionally, an ovarian cystic mass caused the patient to appear pregnant. The patient was treated with the JAK2 inhibitor-ruxolitinib according to peripheral blood cells, although myelofibrosis was improved, the splenomegaly did not reduce. Moreover, hematemesis and melena occasionally occurred. CONCLUSION: Ruxolitinib may clearly reduce splenomegaly. Though myelofibrosis was improved, cirrhosis and splenomegaly in this case continued to worsen. Effective treatment should be discussed.

[The Risk Factors of Thrombosis in Patients with Philadelphia Chromosome-negative Myeloproliferative Neoplasms].

OBJECTIVE: To investigate the overview of thrombosis in myeloproliferative neoplasms(MPN) patients, and to explore the risk factors of thrombosis at diagnosis and during follow-up. METHODS: The clinical data of 388 MPN patients treated in our hospital were collected. The patients were followed up by outpatient and phone. The risk factors of thrombosis were analyzed by statistical methods. RESULTS: Among 388 MPN patients, 161 patients (41.49%) showed thromboses at diagnosis or during follow-up. Among them, 92.55% were arterial thromboses, 146 cases (96.27%) were complicated with thromboses at diagnosis, and 36 cases (11.46%) showed newly thromboses or progression of previous thromboses among the 314 received full follow-up patients. Age (P＜0.001, HR:1.033, 95%CI:1.016-1.051), JAK2V617F mutation (P=0.037, HR:1.72, 95%CI: 1.033-2.862), hypertension (P＜0.001, HR:2.639, 95%CI:1.659-4.197) and hyperlipidemia (P＜0.001, HR:2.659, 95%CI:1.626-4.347) were the independent risk factors affecting thrombosis at diagnosis of the patients. During the follow-up, age (P=0.016, HR:1.032, 95%CI: 1.006-1.059) and previous thrombosis history (P=0.019, HR:2.194, 95%CI: 1.135-4.242) were the independent risk factors affecting the progression of thrombosis at different sites or on the basis of the previous thrombosis in the patients. CONCLUSION: Patients with advanced age, JAK2V617F mutation or complicated with hypertension and hyperlipidemia shows a higher risk of thrombosis at diagnosis, while the patients with advanced age or previous thrombosis history shows a higher risk of progression of thrombosis during the follow-up.

All-trans Retinoic Acid, Arsenic Trioxide, and Anthracycline-based Chemotherapy Improves Outcome in Newly Diagnosed Acute Promyelocytic Leukemia Regardless of FLT3-ITD Mutation Status.

All-trans retinoic acid (ATRA) and pre-upfront arsenic trioxide (ATO) have revolutionized the therapy of acute promyelocytic leukemia (APL). However, internal tandem duplication of FMS-like tyrosine kinase 3 (FLT3-ITD) mutations is associated with increased risk of relapse. The aim of this study was to analyze the prognostic impact of FLT3-ITD on APL patients who received remission induction with ATRA, idarubicin (IDA) and/or ATO, followed by ATRA plus ATO along with anthracycline, as consolidation therapy. A total of 72 patients newly diagnosed with APL were included in this study. 83.3% of the patients achieved complete remission (CR) after induction therapy. FLT3-ITD mutations were detected in 16 (22.2%) patients and closely related to bcr-3 PML-RARa transcript (P<0.001). The 5-year overall survival (OS) rate was 100% in both FLT3-ITDpositive and FLT3-ITDnegative groups, and there was no significant difference in 5-year event-free survival (EFS) between the two groups (78.3% vs. 83.3%, P=0.85). ATRA plus ATO and anthracycline-based chemotherapy achieved great outcome in newly diagnosed APL regardless of the FLT3-ITD mutation status.

lncRNA FOXP4­AS1 predicts poor prognosis and accelerates the progression of mantle cell lymphoma through the miR­423­5p/NACC1 pathway.

Long non­coding RNA (lncRNA) forkhead box P4 antisense RNA 1 (FOXP4­AS1) has been determined to function as an oncogene in various types of cancer. However, the biological function and the underlying mechanisms of FOXP4­AS1 in mantle cell lymphoma (MCL) remain to be uncovered. The expression and the associated clinicopathological characteristics and prognostic significance of FOXP4­AS1 were explored in MCL clinical samples. The effects of FOXP4­AS1 on MCL cellular behaviors, including proliferation, migration and invasion were analyzed using CCK­8, crystal violet and Transwell assays. The downstream molecules of FOXP4­AS1 were explored using bioinformatics analysis and dual luciferase assay. Our results showed that FOXP4­AS1 expression was upregulated in MCL patients, and that the high expression of FOXP4­AS1 was correlated with the unfavorable prognosis of patients. Functionally, while FOXP4­AS1 downregulation inhibited proliferation, migration and invasion of MCL cells, FOXP4­AS1 overexpression had promotive effects on these cellular processes. Mechanistically, FOXP4­AS1 was found to act as a competing endogenous (ce)RNA for miR­423­5p to regulate the expression of nucleus accumbens­associated 1 (NACC1). The negative regulation of FOXP4­AS1 on miR­423­5p compared to that of miR­423­5p on NACC1 was determined at the mRNA or protein levels in MCL cells. Moreover, an inverse expression correlation between FOXP4­AS1 and miR­423­5p, and that between miR­423­5p and NACC1 was confirmed in MCL clinical samples. In addition, rescue assay showed that miR­423­5p upregulation or NACC1 knockdown abolished the promoting effects of FOXP4­AS1 on MCL cell proliferation, migration and invasion. In conclusion, FOXP4­AS1 promotes MCL progression through the upregulation of NACC1 expression by inhibiting miR­423­5p. FOXP4­AS1 may serve as a novel therapeutic target for patients with MCL.

[Clinical Analysis of 269 Ph Chromosome-Negative Myeloproliferative Neoplasms Patients Stratified by Age].

OBJECTIVE: To investigate the difference of clinical characteristics between young patients(age≤40 years old) and middle-older patients(age>40 years old) with the myeloproliferative neoplasms（MPN）. METHODS: The clinical data (gene mutations， peripheral blood routine examinations， imaging examination and past history) of 269 MPN patients was collected and analyzed. RESULTS: In essential thrombocythemia (ET) group, the proportion of triple-negative type in young patients was higher than that in middle-older group, while the peripheral white blood cell（WBC） and platelets（PLT） counts in the first visit were lower. In polycythemia vera (PV) group, the total detection rate of JAK2V617F (80.65%) was lower than that of other research reports. Young patients with PV showed the lower JAK2V617F rate and lower WBC count, compared with the middle-older aged patients. Both CALR and MPL mutations were not found in PV patients. There was only 1 primary myelofibrosis (PMF) patient aged <40 years old. 91.67% of the patients merged splenomegaly and this rate was higher than that of ET or PV patients. It was found that there were a diagnosed familial MPN family and an undiagnosed family， and the youngest patient was only 8 years old. The second-generation gene sequencing detection for them was not carried out. CONCLUSION: Age is an important reference index in the assessment of risks. The MPN patients with different age and types show much difference in gene mutations, peripheral blood cell counts, thrombotic events and sizes of spleen. The onset ages of patients with familial MPN trends to be generational younger.

Therapeutic effects of all trans-retinoic acid combined with transarterial chemoembolization on Walker-256 hepatoma in rats.

In order to investigate the inhibitory effects of all trans-retinoic acid (ATRA) on differentiation and apoptosis of Walker-256 hepatocellular carcinoma cells and the therapeutic effects of ATRA combined with transarterial chemoembolization (TACE) on rat Walker-256 transplanted hepatocarcinoma, Walker-256 hepatocarcinoma cell lines were treated with ATRA at different concentrations. After culture for 48 h, the inhibitory rate of cell proliferation was determined by MTT assay; the changes of Fas and Bcl-2 mRNA expression were determined by RT-PCR, and the expression levels of Caspase3 and Caspase8 proteins were detected by Western blot. Twenty-seven Wistar rat models of hepatocarcinoma were set up successfully by implanting Walker-256 cell lines. The tumor volume at the 11th day after implantation (V(preoperation)) was measured by magnetic resonance imaging (MRI). The 27 rats were randomly and equally divided into three groups, and the therapy scheme was performed as follows: group A (ATRA 0.1 mg+mitomycin 0.05 mL+lipiodol 0.05 mL+gelfoam powder 0.025 mg); group B (mitomycin 0.05 mg+lipiodol 0.05 ml+gelfoam 0.025 mg; group C (0.9% NaCl 0.2 mL). After another 11 days, MRI was performed once again to measure the tumor volume (V(postoperation)). The expression of factor and Ki VIII -67 in the tumor tissues was detected by immunohistochemistry. The results showed that ATRA could suppress proliferation of Walker-256 cell lines. After treatment of Walker-256 cell lines with ATRA, the expression of Fas mRNA was significantly up-regulated and the Bcl-2 mRNA was significantly down-regulated by ATRA at the concentration of 10 mumol/L as compared with the control group (P<0.05). After treatment with 10 mumol/L ATRA for 48 h, the Caspase3 and Caspase8 were significantly activated as compared with the control group (P<0.05). Significant difference existed in growth rate among the three groups (P<0.01) and between either two groups (P<0.05). The expression rate of factor VIII and Ki-67 was gradually increased from group A, group B to group C. The study suggests that ATRA could inhibit the proliferation of Walker-256 cells and the effectiveness of the combined therapy (ATRA+TACE) for treating transplanted hepatoma of rats is superior to that of TACE alone.

Therapeutic Effects of All Trans-retinoitc Acid Combined with Transarterial Chemoembolization on Walker-256 Hepatoma in Rats / 华中科技大学学报（医学）（英德文版）

In order to investigate the inhibitory effects of all trans-retinoitc acid (ATRA) on differentiation and apoptosis of Walker-256 hepatocellular carcinoma cells and the therapeutic effects of ATRA combined with transarterial chemoembolization (TACE) on rat Walker-256 transplanted hepa-tocarcinoma, Walker-256 hepatocarcinoma cell lines were treated with ATRA at different concentrations. After culture for 48 h, the inhibitory rate of cell proliferation was determined by MTT assay; the changes of Fas and Bcl-2 mRNA expression were determined by RT-PCR, and the expression levels of Caspase3 and Caspase8 proteins were detected by Western blot. Twenty-seven Wistar rat models of hepatocarcinoma were set up successfully by implanting Walker-256 cell lines. The tumor volume at the 11th day after implantation (Vpreoperatioi) was measured by magnetic resonance imaging (MRI). The 27 rats were randomly and equally divided into three groups, and the therapy scheme was performed as follows: group A (ATRA 0.1 mg+mitomycin 0.05 mL+lipiodol 0.05 mL+gelfoam powder 0.025 mg); group B (mitomycin 0.05 mg+lipiodol 0.05 ml+gelfoam 0.025 mg; group C (0.9% NaCl 0.2 mL). After another 11 days, MRI was performed once again to measure the tumor volume (Vpostoperation)- The expression of factor VIII and Ki-67 in the tumor tissues was detected by immuno-histochemistry. The results showed that ATRA could suppress proliferation of Walker-256 cell lines. After treatment of Walker-256 cell lines with ATRA, the expression of Fas mRNA was significantly up-regulated and the Bcl-2 mRNA was significantly down-regulated by ATRA at the concentration of 10 umol/L as compared with the control group (P<0.05). After treatment with 10 umol/L ATRA for 48 h, the Caspase3 and Caspase8 were significantly activated as compared with the control group (P<0.05). Significant difference existed in growth rate among the three groups (P<0.01) and between either two groups (P<0.05). The expression rate of factor VIII and Ki-67 was gradually increased from group A, group B to group C. The study suggests that ATRA could inhibit the proliferation of Walker-256 cells and the effectiveness of the combined therapy (ATRA+TACE) for treating transplanted hepatoma of rats is superior to that of TACE alone.

[Expression of CD147 and matrix metalloproteinase-9 in children with non-Hodgkin's lymphoma and its correlation with prognosis].

OBJECTIVE: To investigate the expression of CD147 and matrix metalloproteinase-9 (MMP-9) in children with non-Hodgkin's lymphoma (NHL) and its correlation with clinical stage, tumor size, bone marrow invasion, immunological typing, serum lactate dehydrogenase (LDH) concentration, and prognosis. METHODS: Specimens excised from NHL patients were prepared. Expression of CD147 and MMP-9 were tested by streptavidin-biotin complex (SABC) immunohistochemistry and its correlation with clinical results were analyzed. RESULTS: The positive rate of CD147 expression was 73% (45/62), 17 cases were (-), 11 cases (+), 34 cases (++) and 21 cases (+++). The positive rate of MMP-9 expression was 81% (50/62), 12 cases were (-), 13 cases (+), 18 cases (++) and 19 cases (+++). The Spearman rank correlation analysis indicated that there was a positive correlation between CD147 and MMP-9 expressions in NHL (r(S) = 0.763, P = 0.034). Expression of CD147 was determined in relation to factors that included clinical bone marrow invasion, tumor size, LDH level as well as the clinical stage; expression of MMP-9 had a positive correlation with bone marrow invasion, tumor size and clinical phases. The 5-year survival rates (5YSR) were 78% (22/28) and 45% (15/34) in the cases whose CD147 expression was (-)-(+) and (++)-(+++), respectively, and 5YSR were 84% (21/25) and 43% (16/37) in the cases whose MMP-9 expression was (-)-(+) and (++)-(+++) respectively, the difference was significant. Cox multivariate analysis showed that both CD147 and MMP-9 were important prognostic factors. CONCLUSION: The increased expression of CD147 and/or MMP-9 correlates with a poor clinical outcome in patients with NHL.

[Effects of SODD and survivin on leukemia cell apoptosis induced by chemotherapeutic drugs].

This study was aimed to investigate the changes of silencer of death domains (SODD), survivin, caspase 3, caspase 8 and caspase 9 in the apoptotic process of human leukemia cells induced by chemotherapeutic drugs in order to explore the molecular mechanism of apoptotic modulatory genes and to search for the new target of chemotherapeutic drugs. After Jurkat cells were induced by chemotherapeutic drugs, the translocated phosphatidylserine was labeled with annexin V/PI, and the apoptosis incidence was measured by FCM; The expression changes of SODD, caspase 3, caspase 8 and caspase 9 were determined by Western blot; the changes of survivin mRNA and protein were determined by RT-PCR and immunohistochemistry SABC method respectively. The results indicated that high expressions of SODD and survivin could inhibit apoptotic signaling pathway; VCR down-regulated the function of SODD protein and effectively induced the apoptosis of Jurkat cells in a time-dependent manner and activates caspase 3 through the death receptor-mediated activation of caspase 8, in which caspase 9 and survivin were not degraded. It is concluded that SODD participates in the apoptotic process induced by VCR which induces the Jurkat cell apoptosis by downregulating expression of SODD protein and priming death receptor pathway. In the apoptotic process, the mitochondrion apoptotic pathway is not trigged.

Expression of SODD and P65 in ALL of children and its relationship with chemotherapeutic drugs.

The expression of silence of death domains (SODD) and its clinical significance and relationship with phospho-NF-kappaB-p65 proteins in bone marrow cells of childhood acute lymphoblastic leukaemia (ALL) were explored, and the expression of SODD and phospho-NF-kappaB-p65 in Jurkat cells treated with chemotherapeutic drugs was detected in order to find a new chemotherapeutic target. The expression of SODD and phospho-NF-kappaB-p65 proteins in bone marrow cells was detected by immunohistochemistry in 25 children with ALL. The apoptosis rate was measured by Annexin-V-Fluorescence/PI double-labeling flow cytometry and the expression of SODD and phospho-NF-kappaB-p65 proteins determined by Western blotting in the Jurkat cells. It was found that the expression of SODD and active P65 in ALL was significantly higher than that in normal control group (P<0.05). The expression of the SODD and phospho-NF-kappaB-p65 proteins in the high-risk (HR) group was significantly higher than that in the standard-risk (SR) group (P<0.05). The Pearson rank correlation analysis revealed that there was a positive correlation between SODD and phospho-NF-kappaB-p65 expression (P<0.01, r=0.69). VCR could effectively induce the apoptosis of Jurkat cells, and down-regulate the expression of SODD and phospho-NF-kappaB-p65 proteins in a time-dependent manner, but DNR could not down-regulate the expression of SODD effectively. It was concluded that SODD may be closely related to the clinical classification and prognosis of ALL in children. The expression of SODD and phospho-NF-kappaB-p65 had a definite synergistic relationship with the onset and development of ALL. VCR could down-regulate the expression of SODD and inhibit the NF-kappaB activation, which could recover the sensibility of apoptosis in leukemic cells.

[Expression of Daxx in children with acute leukemia].

OBJECTIVE: To investigate Daxx expression and its clinical significance in children with acute leukemia. METHODS: The expression of Daxx protein was detected by immunohistochemical assay in 50 children with newly diagnosed acute leukemia (34 cases of acute lymphocytic leukemia and 16 cases of acute non-lymphocytic leukemia). Twenty children with normal bone marrow were used as the control group. RESULTS: Daxx protein was expressed in 38.0% of 50 children with acute leukemia, which was significantly higher than that of the control group (5.0%) (P < 0.05). The children with acute non-lymphocytic leukemia had significantly higher Daxx expression levels (62.5%) than those with acute lymphocytic leukemia (26.5%; P < 0.05) as well as the control group (P < 0.05). There were no significant differences in the Daxx expression between acute lymphocytic leukemia children and the control group. Daxx protein was expressed in 55.6% of high risk group of acute lymphocytic leukemia but it was not expressed in standard risk group of acute lymphocytic leukemia (P < 0.05). CONCLUSIONS: Daxx expression is abnormal in children with acute leukemia and associated with some clinical features of acute leukemia, suggesting that it may play an important role in the genesis and development of acute leukemia.