Assessment of knowledge, attitudes, and practices of CML patients and their families toward TKI therapy in China.

The introduction of tyrosine kinase inhibitors (TKIs) has revolutionized chronic myeloid leukemia (CML) treatment. The knowledge, attitude, and practice (KAP) of patients and their families play a significant role in treatment adherence and effectiveness. This study aimed to investigate the KAP of CML patients and their families regarding TKI therapy in China. From November 1 to December 31, 2022, a cross-sectional study was conducted at the Affiliated Huai'an No. 1 People's Hospital in China. A total of 313 CML patients and 268 family caregivers were selected using convenience sampling. Participants answered a self-designed questionnaire. The questionnaire contained demographic/clinical data and assessed KAP toward CML and TKI therapy. Participants exhibited mean KAP scores of 8.91 (55.7%), 33.10 (73.6%), and 2.20 (73.3%), respectively. Family members had higher knowledge and practice scores than patients (both P < .05), with factors such as younger age, urban residency, higher education, employment, higher income, and interaction with peers correlating with better knowledge scores (P < .001). Although participants were well-informed about their diagnosis and medication (>80%), understanding of disease causes (<30%) and treatment prognosis and side effects (<50%) was limited, and cost concerns affected 80.55%. Anxiety and depression were reported more among caregivers (46.64% and 13.8%) than patients (29.71% and 11.51%). While 84.85% adhered to the doctor's instructions, only 68.50% actively sought more CML information. Positive correlations were observed among KAP scores, indicating their interdependence (knowledge-attitude: R = 0.397; knowledge-practice: R = 0.598; attitude-practice: R = 0.353; all P < .001). The findings underscore the importance of tailored education to fill knowledge gaps about CML and the need to address financial concerns and provide psychological support. The positive correlations among knowledge, attitudes, and practices emphasize the need for comprehensive interventions. In conclusion, this study highlights the importance of tailored education, addresses financial concerns, and provides emotional support for CML patients and caregivers in China, despite limitations such as convenience sampling and questionnaire design. Future research should evaluate the effectiveness of educational interventions and long-term outcomes to further enhance the overall well-being of this population.

AKAP12 and IGFBP4 Are Prognostic Factors for Chronic Lymphocytic Leukemia.

INTRODUCTION: The aim of this study was to develop a prognostic model for chronic lymphocytic leukemia (CLL). METHODS: GEO2R was used to retrieve the gene expression data of CLL and normal B cells from the Gene Expression Omnibus (GEO; GSE22529 and GSE50006 datasets) database. Practical Extraction and Report Language was used to extract the gene expression and overall survival (OS) data of CLL patients from the Chronic Lymphocytic Leukemia - ES (CLLE-ES) project in the International Cancer Genome Consortium (ICGC) database. Cox regression with Lasso was used to create and validate a prognostic model for CLL. RESULTS: A total of 267 genes exhibited differential expression between CLL and normal B cells. Cox univariate analysis identified 14 DEGs that correlated with OS. Lasso multivariate evaluation demonstrated that AKAP12 and IGFBP4 are independent prognostic factors for CLL. Kaplan-Meier survival analysis revealed a significant association between the estimated risk score and survival. The area under the receiver operating characteristic curve was calculated to be 0.97, indicating high predictive accuracy. In addition, high AKAP12 and IGFBP4 risk scores were associated with the high incidence of trisomy 12q. CONCLUSION: Taken together, AKAP12 and IGFBP4 are independent prognostic factors for CLL.

HLA-mismatched micro-transplantation as post-remission treatment compared to autologous hematopoietic stem cell transplantation or consolidation with single agent cytarabine for favorable-or intermediate-risk acute myeloid leukemia.

OBJECTIVES: Optimal post-remission treatment for individual favorable and intermediate risk acute myeloid leukemia (AML) patients has not yet been established. Human leukocyte antigen (HLA)-mismatched stem cell microtransplantation (MST), may improve outcomes and avoid graft-versus-host disease in patients with first complete remission of AML. METHODS: We retrospectively analyzed the efficacy, safety, and survival of 63 patients with favorable- or intermediate-risk AML who received MST, autologous stem cell transplantation (ASCT), or cytarabine single agent (CSA) as post-remission treatment from January 2014 to August 2021. RESULTS: The neutrophil recovery time was shorter in the MST group than in the CSA group. The 2-year cumulative incidences of relapse in the MST, ASCT, and CSA groups were 27.27%, 29.41%, and 41.67%, respectively. During follow-up, 21 patients (33.30%) died of relapse, including six (9.52%), five (7.94%), and 10 (15.84%) in the MST, ASCT, and CSA groups, respectively. The estimated 2-year overall survival (OS) and relapse-free survival (RFS) were 62.20% vs. 50.00% (P = 0.101) and 57.10% vs. 50.00% (P = 0.136), in the >60 years MST and CSA groups (P = 0.101). The estimated 2-year OS was 100%, 66.20%, and 69.10% in the MST, ASCT, and CSA groups (MST vs CSA, P = 0.044), meanwhile, the estimated 2-year RFS was 100%, 65.40%, and 59.80% in patients ≤60 years. CONCLUSION: MST, ASCT, and CSA are acceptable post-remission treatments for patients with favorable- and intermediate-risk AML and may not only improve the prognosis of the elderly but also prolong the OS and RFS of favorable- or intermediate-risk patients ≤60 years.

[Efficacy of CLAE Chemotherapy Regimen Followed by Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Relapsed/Refractory Acute Leukemia].

OBJECTIVE: To observe the efficacy and safety of CLAE intensive chemotherapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with relapsed/refractory acute leukemia (R/R AL). METHODS: CLAE regimen [cladribine 5 mg/(m2·d), d 1-5; cytarabine 1.5 g/(m2·d), d 1-5; etoposide 100 mg/(m2·d), d 3-5] followed by allo-HSCT was used to treat 3 R/R AL patients. The patients received CLAE chemotherapy in relapsed or refractory status and underwent bone marrow puncture to judge myelodysplastic state. After an interval of 3 to 5 days, followed by preconditioning regimen for allo-HSCT [fludarabine 30 mg/(m2·d), d -7 to d -3; busulfan 0.8 mg/kg q6h, d -6 to d -3 or d -5 to d -2. If the bone marrow hyperplasia was not active and the blasts were less than 10%, busulfan should be used for 3 days. If the bone marrow hyperplasia was active and the blasts were more than 10%, busulfan should be used for 4 days]. Cyclosporin A, mycophenolate mofetil and short-term methotrexate were used for graft-versus-host disease (GVHD) prevention. After transplantation, the status of minimal residual disease (MRD) and bone marrow chimerism were regularly monitored in all 3 patients, and demethylation drugs or dasatinib were used to prevent recurrence 3 months after transplantation. RESULTS: 2 patients with t(11;19) translocation and relapse/refractory acute myeloid leukemia recurred within 6 months after induction of remission, and received intensive chemotherapy with CLAE regimen followed by haploidentical allo-HSCT and unrelated donor allo-HSCT, respectively. The two patients both relapsed 6 months after transplantation, then achieved complete remission by donor lymphocyte infusion, interferon, interleukin-2 and other methods, and disease-free survival was 2 years after transplantation. The other patient was chronic myelogenous leukemia who developed acute lymphoblastic leukemia during oral administration of tyrosine kinase inhibitor, accompanied by T315I and E255K mutations in ABL1 kinase region and additional chromosomal abnormalities. After morphological remission by induction chemotherapy, central nervous system leukemia was complicated. Intensive chemotherapy with CLAE regimen followed by sibling allo-HSCT was performed in the positive state of MRD. The patient relapsed 3 months after transplantation, and achieved remission after chimeric antigen receptor T-cell (CAR-T) therapy, however, he died 5 months after transplantation because of severe cytokine release syndrome (CRS) and GVHD. CONCLUSION: CLAE regimen followed by allo-HSCT may be an effective salvage treatment option for R/R AL patients to prolong the overall survival.

[Effect of CXCR4 on the Treatment Response and Prognosis of Carfilzomib in Multiple Myeloma].

OBJECTIVE: To explore the effect of CXCR4 on the treatment response and prognosis of Carfilzomib (CFZ) in multiple myeloma. METHODS: Dataset GSE69078 based on microarray data from two CFZ-resistant MM cell lines and their corresponding parental cell lines (KMS11-KMS11/CFZ and KMS34-KMS34/CFZ) were downloaded from Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) were identified, and Protein-protein interaction (PPI) network was established to identify the key genes involved in CFZ resistance acquisition. Finally, the prognostic roles of the CFZ risistance key genes in MM using MMRF-CoMMpass data study was verified. RESULTS: 44 up-regulated and 46 down-regulated DEGs were identified. Top 10 hub genes (CCND1, CXCR4, HGF, PECAM1, ID1, HEY1, TCF4, HIST1H4J, HIST1H2BD and HIST1H2BH) were identified via Protein-protein interaction (PPI) network analysis. The CoMMpass data showed that high CXCR4 expression showed correlation to relative higher relapse and progress rates and the overall survival was significant decreased in high CXCR4 patients (P=0.013). CONCLUSION: CXCR4 perhaps plays a crucial role in CFZ acquired resistance, which might help identifying potential CFZ-sensitive patients before treatment and providing a new therapeutic target in CFZ-resistant MM.

Epidemiologic Characteristics, Prognostic Factors, and Treatment Outcomes in Primary Central Nervous System Lymphoma: A SEER-Based Study.

OBJECTIVE: This study was conducted in order to study the clinical characteristics, prognostic factors, and treatment outcomes in patients with primary central nervous system lymphoma (PCNSL). MATERIALS AND METHODS: The data of a total of 5,166 PCNSL patients diagnosed between 2000 and 2018 from the Surveillance, Epidemiology, and End Results (SEER) database were obtained. RESULTS: The mean age was 63.1 ± 14.9 years, with a male to female ratio of 1.1:1.0. The most common histologic subtype was diffuse large B-cell lymphoma (DLBCL) (84.6%). The 1-, 3-, and 5-year overall survival (OS) rates were 50.1%, 36.0%, and 27.2%, respectively, and the corresponding disease-specific survival (DSS) rates were 54.4%, 41.3%, and 33.5%, respectively. Multivariate analysis with Cox regression showed that race, sex, age, marital status, surgical resection, and chemotherapy were independent prognostic factors for OS and DSS, but radiotherapy was only for OS. Nomograms specially for DLBCL were established to predict the possibility of OS and DSS. The concordance index (C-index) values of OS and DSS were 0.704 (95% CI 0.687-0.721) and 0.698 (95% CI 0.679-0.717), suggesting the high discrimination ability of the nomograms. CONCLUSION: Surgical resection and/or chemotherapy was favorably associated with better OS and DSS. However, radiotherapy was not beneficial for OS and DSS in the long term. A new predictive nomogram and a web-based survival rate calculator we developed showed favorable applicability and accuracy to predict the long-term OS for DLBCL patients specifically.

High expression of TARP correlates with inferior FLT3 mutations in non-adolescents and young adults with acute myeloid leukaemia.

OBJECTIVES: Acute myeloid leukaemia (AML) is a haematopoietic malignancy with a dismal outcome. Consequently, risk stratification based on more effective prognostic biomarkers is crucial to make accurate therapy decisions. T cell receptor gamma alternative reading frame protein (TARP) has been reported in prostate and breast cancers, but its correlation with AML remains unclear. METHODS: Differential expression of TARP mRNA in different AML subtypes was analysed using the UALCAN online platform. Its relationship with baseline clinical attributes, survival and efficacy were analysed based on three GSE1159, GSE425 and GSE6891 microarray datasets downloaded from Gene Expression Omnibus (GEO) and Oncomine databases. Quantitative real-time PCR was performed to determine mRNA levels of TARP in bone marrow mononuclear cells (BMMCs) isolated from AML patients. RESULTS: TARP was significantly overexpressed in AML patients. In AML, relatively low TARP expression was associated with the CBFß-MYH11 fusion gene. The proportion of FLT3 mutations was significantly higher in non-adolescent and young adult (non-AYA, >39 years of age) AML patients who had high TARP levels but not in AYA (15-39 years) patients. High expression of TARP was related to poor outcome by univariate analysis but not by multivariate analysis and unsatisfactory therapeutic effects, which could be overcome by haematopoietic stem cell transplantation (HSCT). CONCLUSION: Our findings suggest that TARP might be a potential prognostic marker of AML and serve as a promising immunotherapeutic target.

[Efficacy of Micro-Transplantation Consolidation Therapy for Patients with Acute Myeloid Leukemia after Complete Remission].

OBJECTIVE: To investigate the efficacy and safety of micro-transplantation in acute myeloid leukemia (AML). METHODS: The clinical data of 13 adult AML patients who received micro-transplantation as consolidation therapy from July 2014 to October 2019 was retrospectively analyzed, and the adverse reactions and efficacy of micro-transplantation were followed up. RESULTS: Eight patients received micro-transpantation were still in complete remission, 5 patients relapsed after micro-transplantation, 1 of them received umbilical cord blood micro-transplantation after remission by reinduction, and all of the 13 patients have survived till now. The median overall survival time was 13 months, and the median relapse-free survival time was 12 months. All 13 patients developed grade 2-4 hematological adverse reactions. The median recovery time of neutrophils and platesets was 13 (11-15) and 15 (13-17) days, respectively. None of the 13 patients developed acute or chronic graft versus host disease. Twelve patients suffered from different infections, however, there were no serious organ function injury complications happened. CONCLUSION: The micro-transplomtation of HLA-incompatible stem cells derived from peripheral blood or umbilical and blood is an effective regimen for the consolidation therapy of AML, especially for the patients suffered from low and moderate risk of AML or the aged AML patients.

Successful treatment of two relapsed patients with t(11;19)(q23;p13) acute myeloid leukemia by CLAE chemotherapy sequential with allogeneic hematopoietic stem cell transplantation: Case reports.

The prognosis of patients with relapsed/refractory acute myeloid leukemia (R/R AML) is poor, with a 3-year overall survival rate of 10%. Patients with translocation (t)(11;19)(q23;p13) have a higher risk of relapse and there is no optimal regimen for these patients. The present study treated two young patients with t(11;19)(q23;p13) AML, who relapsed after one or two cycles of consolidation, with a salvage treatment consisting of sequential cladribine, cytarabine and etoposide (CLAE) and allogeneic hematopoietic stem cell transplantation (allo-HSCT). Both neutrophil and platelet engraftments were achieved within 15 days, and no severe transplant-related complications and graft-versus-host diseases were observed. Following allo-HSCT, both patients achieved complete hematologic and cytogenetic remission. Decitabine was used for the prophylaxis of relapse. The two patients remained alive and disease-free for 100 days following allo-HSCT. The results presented here suggest that CLAE regimen sequential with allo-HSCT may be effective in treating patients with R/R AML, with t(11;19)(q23;p13). However, further studies and a larger sample size are required to validate the effectiveness of this treatment regimen.

[Significance of Targeted Sequencing Assay for Patients with Suspected Myeloid Malignancies].

OBJECTIVE: To investigate the clinical significance of the targeted next-generation sequencing assay for patients with suspected myeloid malignancies. METHODS: A total of 39 hematopenia patients with suspected myeloid malignamies in Department of Hematology of The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University from January 2018 to April 2019 were treated, 20 hot spot genes of myelodysplastic syndrome (MDS) were detected. RESULTS: Regarding the diagnostic type, there were 7 cases of idiopathic cytopenia of undetermined significance (ICUS), 8 cases of clonal cytopenias of undetermined significance (CCUS) and 24 cases of myeloid myeloid malignancies which included 18 cases of MDS, 4 cases of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) and 2 cases of acute myeloid leukemia. Positive mutation was detected in 70.8% (17/24) of myeloid malignancy patients , and 72.7% (16/22) in MDS and MDS/MPN patients. The main mutation types were ASXL1, TET2 and RUNX1. Compared with gene negative group, there were no significant differences in sex, age (＜60 years old or ≥60 years old), proportion of bone marrow blast cells (＜5% or≥5%) and cytogenetics (good, medium and poor) (P＞0.05). Furthermore, all 8 CCUS patients showed positive mutation, and the incidence of double or multiple mutation in CCUS group was significantly lower than that of the MDS and MDS/MPN group (37.5% vs 54.5%) (P=0.002). The mutation types between the two groups were similar, and there was no significant difference in variant allele frequency (P＞0.05). CONCLUSION: Our results suggest that there are high rates of double or multiple mutations in myeloid malignancies, especially in patients with MDS and MDS/MPN. Targeted sequencing assay can improve the diagnosis of myeloid malignancies, and guide clinical treatment.

Acute Myeloid Leukemia with NUP98-RARG Gene Fusion Similar to Acute Promyelocytic Leukemia: Case Report and Literature Review.

Retinoic acid receptor gamma (RARG) belongs to the nuclear receptor superfamily and has 90% homology to RAR alpha (RARA) and RAR beta. The promyelocytic leukemia (PML)-RARA fusion gene has been implicated in acute promyelocytic leukemia (APL). RARG gene rearrangement has been identified in a rare subtype of acute myeloid leukemia (AML) that resembles APL. To date, only 10 cases of gene rearrangements involving RARG (nucleoporin [NUP]98-RARG, promyelocytic leukemia protein-RARG, cleavage and polyadenylation-specific factor 6-RARG, or nucleophosmin [NPM]1-RARG-NPM1) have been reported. These patients show characteristics similar to APL, including bone marrow morphology, coagulation abnormality, and immunophenotype; however, they are resistant to all-trans retinoic acid and arsenic trioxide treatment. Moreover, there is no optimal therapeutic regimen for this subtype of AML. In this study, we report the clinical presentation and experimental findings of a case of AML with NUP98-RARG gene fusion similar to APL and review other cases of RARG gene rearrangement described in the literature.

[Clinical Analysis of 66 Patients with Essential Thrombocytopenia].

OBJECTIVE: To investigate the clinical characteristics of essential thrombocytopenia (ET) patients with positive mutations including JAK2, CALR, MPL, or negative mutations. METHODS: A total of 66 newly diagnosed ET cases from January 2016 to December 2018 in Department of Hematology, Huaian No.1 People's Hospital affiliated to Nanjing Medical University were analyzed. Statistical analysis data included the patient's sex, age, symptoms, thrombosis and embolism events, spleen omegaly, platelet count (Plt), leukocyte (WBC) count, hemoglobin (Hb), fibrinogen (FIB), thrombus elastic diagram (TEG), serum potassium, blood glucose (GLU), lactate dehydrogenase (LDH), JAK2, CALR and MPL mutations, treatment options, and efficacy. RESULTS: All the patients were not MPL-positive, and divided in three groups: JAK2 mutation (46 cases, 69.7%), CALR mutation (9 cases, 13.6%) and gene negative mutation (11 cases, 16.7%) group. The average age of patients in the JAK2 mutation group was 63.2 years old, and significantly higher than that in the CALR mutation group (51.8 year) and gene negative group (50.2 year) (P＜0.05). Compared with the JAK2 mutation group and gene negative group, the CALR mutation group had lower WBC count (6.3×109/L vs 13.79×109/L) (P=0.003) (6.3×109/L vs 9.70×109/L) (P=0.009). Also the Hb level of patients in CALR mutation group was lower than the JAK2 mutation group (121.22 g/L vs 136.2 g/L) (P=0.036). However, there was higher tumor burden in the CALR mutation group, compared with the gene negative mutation group (300.11 U/L vs 227.4 U/L) (P=0. 033). There was no significant difference among the three groups, such as the Plt counts, serum potassium level, GLU level and FIB level (P＞0.05). In addition, thrombus and embolism appeared in 30.3% (20/66) cases. 18.2% (12/66) cases were complicated with hyperkalemia, which significantly correlated with Plt counts (r=0.518). TEG was performed in 34 patients, of which 41.2% (14/34) had abnormal TEG and 55.9% (19/34) were accompanied by Plt count ＞ 1 000 ×109/L, but there was no significant correlation between them (r=0.134). After routine clinical treatment, all the 66 cases achieved partial or complete hematological remission, but the disease usually repeated. Until now 4.5% (3/66) cases had been converted to myelofibrosis (MF) all with JAK2 mutation, but without advancing to acute myeloid leukemia. CONCLUSION: ET patients with JAK2 mutation have higher incidence, moreover were in older age. However, the patients with CALR mutations display lower WBC count and Hb level, but higher tumor burden. In short, the multiple gene mutations of ET showed different clinical features closely relates with the prognosis, thus providing guidance for the clinical diagnosis and treatment.

Impact of anemia on the outcomes of chronic phase chronic myeloid leukemia in TKI era.

Objectives: It is common of chronic phase chronic myeloid leukemia (CML-CP) patients coexisting anemia at diagnosis, but the role of anemia on the prognosis is not clear. This study aims to explore impact of anemia on outcomes of CML-CP patients in TKI era.Methods: In the retrospective study, 258 newly diagnosed CML patients treated with TKIs were enrolled. Patients with moderate anemia (Hb ≤ 90 g/L) and non-moderate anemia (Hb > 90 g/L) were compared.Results: The incidence of moderate anemia at the time of CML diagnosis was 34.8%. Compared with patients with non-moderate anemia, patients with moderate anemia had higher proportion of intermediate-high Sokal risks and more aggressive characteristics such as higher WBC counts, higher percent of myeloblasts and basophils. However, there were no statistical differences in terms of optimal response rates, 5-year PFS and OS between the two groups.Conclusion: Moderate anemia is a common concomitant symptom in CML-CP patients and is associated with high-risk CML, but its occurrence does not affect the survival of CML-CP patients in TKI era.

[Therapeutic Response and Prognosis of Adult Acute Myeloid Leukemia with Chromosome Karyotype Abnormalities].

OBJECTIVE: To investigate the efficacy and prognosis of acute myeloid leukemia (AML) patients with chromosome karyotype abnormalities. METHODS: The clinical features and treatment responses of 91 patients with AML were collected and analyzed retrospectively. The efficacy and survival rate of the AML patients with normal and abnormal chromosome karyotype were compared. RESULTS: Chromosome translocations and monosomal karyotypes were the main heterogeneity of AML. There was no significant difference in complete remission rate and overall response rate between the normal and abnormal karyotype groups, but the recurrence rate was higher in abnormal karyotype group. There was no significant difference in response of AML patients received the standard "3+7 regimen" and pre-excitation chemotherapy in the treatment of normal and abnormal karyotype groups. The relapse free survival time (RFS) was longer in the normal karyotype group, but there was no significant difference in overall survival time (OS). CONCLUSION: The abnormal karyotype of AML is an independent prognostic factor, monosomal karyotype shows a poor prognosis, and the recurrence rate in AML patients with monosomal karyotype is higher.

Prognosis and outcome of patients with acute myeloid leukemia based on FLT3-ITD mutation with or without additional abnormal cytogenetics.

The FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) gene mutation is present in ~20% of patients with de novo acute myeloid leukemia (AML). Patients with an FLT3-ITD mutation have a poor prognosis. However, the prognostic function of FLT3-ITD combined with other cytogenetic abnormalities are not clear. In the present study, a retrospective analysis of 103 newly diagnosed patients with AML was performed. The results revealed that the overall survival (OS) and recurrence-free survival (RFS) times were significantly longer in patients with an FLT3-ITD mutation combined with other favorable risk genes, compared with in those patients with a single FLT3-ITD mutation (P=0.0361 and P=0.0426). Sorafenib combined with chemotherapy significantly improved the overall response rate (ORR) when compared with mono-chemotherapy (P=0.039), but no significant differences were observed in the OS and RFS. In conclusion, favorable-risk cytogenetics may improve the clinical outcomes of patients with FLT3-ITD-mutated AML, but adverse-risk cytogenetics may not further worsen the prognosis. Sorafenib combined with chemotherapy may increase the ORR but would not result in a longer OS and RFS.

Long-term effect of all-trans retinoic acid and arsenic trioxide sequential maintenance in patients with acute promyelocytic leukemia.

The specific prognostic factors and the long-term effects of different treatment options in APL remain unclear. In this retrospective study, 70 APL patients were treated with ATRA + DNR/DA or ATRA + ATO regimens for induction therapy and DA or ATRA + ATO for consolidation and maintenance therapy. The prognostic factors and treatment effects on outcome were analyzed. Results showed that the 5-year OS in low-intermediate risk and high risk groups were 95.63% and 100%, and the 5-year RFS were 95.34% and 100%, respectively, the early mortality rate was 4.28%. No significant difference was found on OS and RFS with different regimens, but side-effects and treatment-related mortality rates were lower in ATRA + ATO group. CD34 expression, FLT3-ITD mutation and PML-RARA isoform had no significance on OS and RFS. In conclusion, cytogenetic and molecular abnormalities had no influence on effect of APL patients; ATRA + ATO sequential maintenance may alleviate complications, treatment-related mortality, and the previously high risk factors.

miR-134 increases the antitumor effects of cytarabine by targeting Mnks in acute myeloid leukemia cells.

The relapse and resistance to cytarabine (Ara-C) therapy is still a dominating obstacle to the successful clinical treatment of acute myeloid leukemia (AML). Recent studies have shown that dysregulation of miRNAs might modulate the resistance of cancer cells to anticancer drugs; yet, the mechanism is not fully understood. In this study, we showed a significant downregulation of miR-134 in human multidrug-resistant leukemia cells and relapsed/refractory AML patient samples. Overexpression of miR-134 sensitized K562/A02 and HL-60/ADM cells to Ara-C, inhibited cell colony formation, and enhanced the ability of Ara-C to induce apoptosis. Mechanistic analyses revealed that Mnks was a putative target of miR-134, which was inversely correlated with miR-134 expression in human multidrug-resistant leukemia cells and relapsed/refractory AML patient samples. Further investigation showed that miR-134 increased the anti-tumor effects of Ara-C through inhibiting phosphorylation of eukaryotic initiation factor 4E and downregulating Mcl-1 and bcl2, which was independent of p38 and Erk1/2 activation. Taken together, our results demonstrate that miR-134 plays a pivotal role in AML Ara-C resistance through increasing cell sensitivity to Ara-C and promoting apoptosis by targeting Mnks.

[Influence of Co-inhibiting mTORC2 and HSP90 on Proliferation Apoptosis of Multiple Myeloma Cells].

UNLABELLED: Objective：To explore the influence of co-inhibiting mTORC2 and HSP90 on the proliferation and apoptosis of multiple myeloma(MM) cell line U266. METHODS: During culture, the human MM cell line U266 were treated with 20 nmol/L of rapamycin, 600 nmol/L 17-AAG, 20 nmol/L of rapamycin + 600 nmol/L 17-AGG and phosphate-buffered saline (PBS), then the growth inhibition rate, morphologic changes, apoptosis rate and the expression of caspase 3 and ATK protein in U266 cells were compared and analyzed. RESULTS: The rapamycin and 17-AAG both could inhibit the growth of U266 cells, while the inhibitory effect of rapamycin in combination with 17-AAG on growth of U266 cells was significantly higher them that of rapamycin and 17-AAG alone and control (PBS); the apoptosis rate of U266 cells treated with rapamycin, 17-AAG and their combination was higher than that of control PBS groups, and the efficacy of 2 drug conbination was higher than that of control PBS group, and the efficacy of 2 drug combination was superior to single drug. The expression levels of caspase 3 and ATK in U266 cells treated with rapamycin, 17-AAG and their combination were higher and lower than those in control group respectively, and the efficacy of 2 drug combination was superior to signle drug. There were significant difference between them (P<0.05). CONCLUSION: The co-inhibition of mTORC2 and HSP90 can suppress the proliferation and induce the apoptosis of MM cells.

[HSP90 Inhibitor 17-AAG Inhibits Multiple Myeloma Cell Proliferation by Down-regulating Wnt/ß-Catenin Signaling Pathway].

OBJECTIVE: To investigate the inhibitory effect of HSP90 inhibitory 17-AAG on proliferation of multiple myeloma cells and its main mechanism. METHODS: The multiple myeloma cells U266 were treated with 17-AAG of different concentrations (200, 400, 600 and 800 nmol/L) for 24, 48, and 72 hours respectively, then the proliferation rate, expression levels of ß-catenin and C-MYC protein, as well as cell cycle of U266 cells were treated with 17-AAG and were detected by MTT method, Western blot and flow cytometry, respectively. RESULTS: The 17-AAG showed inhibitory effect on the proliferation of U266 cells in dose- and time-depetent manners (r = -0.518, P < 0.05 and r = -0.473, P < 0.05), while the culture medium without 17-AAG displayed no inhibitory effect on proliferation of U266 cells (P > 0.05). The result of culturing U266 cells for 72 hours by 17-AAG of different concentrations showed that the more high of 17-AAG concentration, the more low level of ß-catenin and C-MYC proteins (P < 0.05); At same time of culture, the more high of 17-AAG concentration, the more high of cell ratio in G1 phase (P < 0.05), at same concentration of 17-AAG, the more long time of culture, the more high of cell ratio in G1 phase (P < 0.05). CONCLUSION: The HSP90 inhibitory 17-AAG can inhibit the proliferation of multiple myeloma cells, the down-regulation of Wnt/ß-catenin signaling pathway and inhibition of HSP90 expression may be the main mechnisms of 17-AAG effect.