The CDK4/6 inhibitor Palbociclib synergizes with ATRA to induce differentiation in AML.

Differentiation therapy based on ATRA almost cured acute promyelocytic leukemia (APL). However, it is disappointing that ATRA is not effective against other acute myeloid leukemia (AML) subtypes. Developing new and effective anti-AML therapies that promote leukemia differentiation is necessary. The CDK4/6-cyclin D pathway is a key initiator of the G1/S phase transition, which determines cell fate. Herein, we investigated whether the CDK4/6 inhibitor palbociclib would synergize with ATRA to promote leukemia differentiation in vitro and in vivo. Our findings revealed that CDK4/6-cyclin D pathway genes were aberrantly expressed in AML, and we observed that palbociclib sensitized AML cells to ATRA-induced morphologic, biochemical, and functional changes indicative of myeloid differentiation. The combination of palbociclib and ATRA attenuated AML cell expansion in vivo. These enhanced differentiation effects may be associated with the regulation of transcription factors, including RARα, E2F1, and STAT1. Overall, our findings demonstrate that CDK4/6 inhibition sensitizes AML cells to ATRA and could guide the development of novel therapeutic strategies for AML patients.

Accumulation of circulating myeloid-derived suppressor cell subsets: predicting poor clinical efficacy and prognosis through T cell suppression in non-Hodgkin's lymphoma.

Myeloid-derived suppressor cells (MDSCs) are implicated in the regulation of immune responses closely associated with poor clinical outcomes in cancer. However, the MDSC subtypes in non-Hodgkin's lymphoma (NHL) have not been systematically investigated. So, we investigated the percentage of MDSC subsets in 78 newly diagnosed NHL patients by flow cytometry. The results showed that all MDSC subsets increased in NHL patients compared with healthy donors. Notably, MDSCs, monocytic MDSCs, and CD14 + CD66b + MDSCs significantly increased in NHL patients compared with those with lymphadenitis donors. polymorphonuclear MDSCs (PMN-MDSCs), early-stage MDSCs (e-MDSCs), and the International Prognostic Index were independent risk factors for poor clinical efficacy and were involved in constructing the nomogram for predicting clinical efficacy. Progression-free survival (PFS) was significantly shorter in patients with high level of MDSC subsets, and PMN-MDSCs emerged as an independent prognostic factor for PFS. PMN-MDSCs, e-MDSCs, and the International Prognostic Index were involved in constructing the nomogram for predicting PFS. Patients with a higher percentage of MDSCs, PMN-MDSCs, e-MDSCs, and CD14 + CD66b + MDSCs experienced a shorter overall survival compared with those with lower percentages. In addition, research on mechanisms found that T cell function was suppressed and mediated by the expansion of MDSCs via involving arginase-1 and interleukin-10 in vitro and in vivo. In conclusion, our study demonstrates that the increased circulating MDSC subsets predict poor clinical efficacy and prognosis in NHL, potentially involving T cell suppression through MDSC subset expansion. These findings indicate the potential of MDSC subsets as comprehensive diagnostic, prognostic biomarkers, and therapeutic targets for NHL.

The roles and mechanisms of TGFB1 in acute myeloid leukemia chemoresistance.

Relapsed or Refractory (R/R) Acute Myeloid Leukemia (AML) patients usually have very poor prognoses, and drug-resistance is one of the major limiting factors. In this study, we aimed to explore the functions of Transforming Growth Factor-ß1 (TGFB1) in AML drug-resistance. First, TGFB1 levels in serum and bone marrow are higher in R/R patients compared with newly diagnosed patients, this phenomenon could be due to different sources of secreted TGFB1 according to immunohistochemistry of marrow biopsies. Similarly, TGFB1 expression in AML drug-resistant cell lines is higher than that in their parental cell lines, and blocking the TGFB signaling pathway by specific inhibitors decreased resistance to chemotherapeutic agents. On the other hand, exogenous TGFB1 can also promote AML parental cells senescence and chemotherapy resistance. Next, we found SOX4 level is upregulated in drug-resistant cells, and parental cells treated with exogenous TGFB1 induced upregulation of SOX4 levels. Interference of SOX4 expression by siRNA diminished the TGFB1-induced sensitivity to chemotherapeutic agents. Finally, we conduct metabolomic analysis and find Alanine, aspartate and glutamate metabolism pathway, and Glycerophospholipid metabolism pathway are decreased after inhibiting TGFB signaling pathway or interfering SOX4 expression. This study concludes that TGFB1 level in R/R AML patients and drug-resistant strains is significantly increased. Blocking the TGFB signaling pathway can enhance the chemosensitivity of drug-resistant cells by suppressing SOX4 expression and metabolic reprogramming.

Super-Enhancer-Associated nine-gene prognostic score model for prediction of survival in chronic lymphocytic leukemia patients.

Chronic lymphocytic leukemia (CLL) is a type of highly heterogeneous mature B-cell malignancy with various disease courses. Although a multitude of prognostic markers in CLL have been reported, insights into the role of super-enhancer (SE)-related risk indicators in the occurrence and development of CLL are still lacking. A super-enhancer (SE) is a cluster of enhancers involved in cell differentiation and tumorigenesis, and is one of the promising therapeutic targets for cancer therapy in recent years. In our study, the CLL-related super-enhancers in the training database were processed by LASSO-penalized Cox regression analysis to screen a nine-gene prognostic model including TCF7, VEGFA, MNT, GMIP, SLAMF1, TNFRSF25, GRWD1, SLC6AC, and LAG3. The SE-related risk score was further constructed and it was found that the predictive performance with overall survival and time-to-treatment (TTT) was satisfactory. Moreover, a high correlation was found between the risk score and already known prognostic markers of CLL. In the meantime, we noticed that the expressions of TCF7, GMIP, SLAMF1, TNFRSF25, and LAG3 in CLL were different from those of healthy donors (p < 0.01). Moreover, the risk score and LAG3 level of matched pairs before and after treatment samples varied significantly. Finally, an interactive nomogram consisting of the nine-gene risk group and four clinical traits was established. The inhibitors of mTOR and cyclin-dependent kinases (CDKs) were considered effective in patients in the high-risk group according to the pRRophetic algorithm. Collectively, the SE-associated nine-gene prognostic model developed here may be used to predict the prognosis and assist in the risk stratification and treatment of CLL patients in the future.

Comparison of first-line treatments for elderly patients with diffuse large B-cell lymphoma: A systematic review and network meta-analysis.

Background: The incidence of DLBCL in elderly patients has been gradually increased. Considering their comorbidities and performance status, the first-line standard treatment hasn't been determined for the elderly. Methods: We performed a systemic review and network meta-analysis to compare the efficacy and safety of all eligible regimens as first line treatment for elderly patients with DLBCL. We searched PubMed, Cochrane Library, and Embase Library proceedings up to March 2022. Results: Our search yielded thirteen trials including 1839 patients. R2CHOP21 showed the best PFS with a statistical difference and the most favorable OS without a statistical difference. RCOMP showed the most clinical benefits in EFS, CR and OR with no significant difference. The point estimate was in favored improved DFS with RCHOP14 than RCHOP21, although this was not statistically significant. In a subgroup analysis concerning 3-4 grade AEs revealed R-COMP was associated with a decrease in grade III/IV neutropenia and cardiac toxic events; RminiCEOP was associated with the lower rates of 3-4 grade anemia, thrombocytopenia and infection; RCHOP21 had the lowest rate of 3-4 grade AE of neurotoxicity. Conclusion: The findings of our meta-analysis indicated that R2CHOP21 provided the best disease control in PFS and represented an optimal first-line treatment option in the elderly with DLBCL. Furthermore, RCOMP, RminiCEOP and RCHOP21 exhibited lower rates in different 3-4 grade AEs and might be reasonable treatment options in the elderly with poor general conditions.

Integrated bioinformatics analysis reveals dynamic candidate genes and signaling pathways involved in the progression and prognosis of diffuse large B-cell lymphoma.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous malignancy with varied outcomes. However, the fundamental mechanisms remain to be fully defined. AIM: We aimed to identify core differentially co-expressed hub genes and perturbed pathways relevant to the pathogenesis and prognosis of DLBCL. METHODS: We retrieved the raw gene expression profile and clinical information of GSE12453 from the Gene Expression Omnibus (GEO) database. We used integrated bioinformatics analysis to identify differentially co-expressed genes. The CIBERSORT analysis was also applied to predict tumor-infiltrating immune cells (TIICs) in the GSE12453 dataset. We performed survival and ssGSEA (single-sample Gene Set Enrichment Analysis) (for TIICs) analyses and validated the hub genes using GEPIA2 and an independent GSE31312 dataset. RESULTS: We identified 46 differentially co-expressed hub genes in the GSE12453 dataset. Gene expression levels and survival analysis found 15 differentially co-expressed core hub genes. The core genes prognostic values and expression levels were further validated in the GEPIA2 database and GSE31312 dataset to be reliable (p < 0.01). The core genes' main KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichments were Ribosome and Coronavirus disease-COVID-19. High expressions of the 15 core hub genes had prognostic value in DLBCL. The core genes showed significant predictive accuracy in distinguishing DLBCL cases from non-tumor controls, with the area under the curve (AUC) ranging from 0.992 to 1.00. Finally, CIBERSORT analysis on GSE12453 revealed immune cells, including activated memory CD4+ T cells and M0, M1, and M2-macrophages as the infiltrates in the DLBCL microenvironment. CONCLUSION: Our study found differentially co-expressed core hub genes and relevant pathways involved in ribosome and COVID-19 disease that may be potential targets for prognosis and novel therapeutic intervention in DLBCL.

Red blood cell distribution width and platelet counts are independent prognostic factors and improve the predictive ability of IPI score in diffuse large B-cell lymphoma patients.

BACKGROUND: Elevated red blood cell distribution width (RDW) and decreased platelet count (PLT) can be clinically relevant to the prognosis in cancer patients. However, their prognostic values in patients with diffuse large B-cell lymphoma (DLBCL) need to be further explored. METHODS: Healthy donors (n = 130) and patients with DLBCL (n = 349) were included and evaluated retrospectively in this study. The prognostic influence of clinical and pathological factors including RDW and PLT on overall survival (OS) and progression-free survival (PFS) were studied by Kaplan-Meier curves. To evaluate the independent prognostic relevance of RDW and PLT, univariate and multivariate Cox proportional hazards regression models were applied. The adjusted IPI model was established based on the results of multivariate analysis, and verified by Harrell's C statistical analysis. RESULTS: Kaplan-Meier curves indicated that an elevated RDW value and thrombocytopenia are poor factors for OS (P < 0.001, P = 0.006) and PFS (P = 0.003, P < 0.001) in DLBCL patients. Multivariate analysis confirmed that elevated RDW value (HR = 2.026, 95%CI = 1.263-3.250, P = 0.003) and decreased PLT count (HR =1.749, 95%CI = 1.010-3.028, P = 0.046) were both independent prognostic factors. The c-index of IPI and NCCN-IPI were increased when RDW level and PLT were supplemented in our cohort. CONCLUSIONS: Our study shows that elevated RDW level and decreased PLT are independent poor prognostic factors in newly diagnosed DLBCL patients. Adding RDW and PLT to the IPI score may improve its predictive ability, and the adjusted IPI may be more powerful in predicting the survival of DLBCL patients in the rituximab era.

The level of Krüppel-like factor 8 expression predicts prognosis and metastasis in various carcinomas.

BACKGROUND AND OBJECTIVE: Krüppel-like factor 8 (KLF8), a transcription factor, belongs to the KLF8 family. Currently, studies have shown that KLF8 is highly expressed in some tumors. However, the prognostic value and metastasis of KLF8 in cancers remain unclear. For the first time, we conducted meta-analysis to explore the relationship between KLF8 expression with prognosis and metastasis in various carcinomas patients. METHODS: Web of Science, PubMed, Embase, and Cochrane Library were systematically searched for eligible articles. Pooled hazard ratios (HRs) and their 95% confidence intervals (95% CIs) were calculated to evaluate the prognostic value and metastasis of KLF8 expression in human cancer patients. RESULTS: The result revealed that highly expression level of KLF8 was significantly associated with poor overall survival (OS) (HR = 1.56, 95% CI: 1.26-1.87). Meanwhile, this significant correlation was also observed in subgroup analysis stratified by cancer types, source of HR, sample size, follow-up (months). In addition, highly expression of KLF8 was also closely associated with metastasis (HR = 1.37, 95% CI: 0.57-2.17) and tumor node metastasis stage (HR = 1.58, 95% CI: 0.90-2.25) in carcinomas. CONCLUSION: In summary, our meta-analysis indicates that overexpression of KLF8 may be associated with poor prognosis and higher incidence of metastasis in various carcinomas, and KLF8 may be used as a prognostic and metastatic indicator in human cancers.

The Significance of Long Non-coding RNA HULC in Predicting Prognosis and Metastasis of Cancers: a Meta-Analysis.

Long non-coding RNAs (lncRNAs) have been demonstrated that they not only play important roles in tumorgenicity but also associate with cancer prognosis. Recently, highly up-regulated in liver cancer (HULC) is abnormally expressed in liver cancer and other cancers, and participated in cancers progression; however, it is unclear whether its expression is associated with prognosis. Here, we performed a meta-analysis and systematic review to evaluate the prognostic value and metastasis of HULC in various cancer patients. The meta-analysis was performed using a systematic search of PubMed, Web of Science, ScienceDirect and Wiley Online Library database to eligible studies. The pooled hazard ratios (HRs) with a 95% confidence interval (95% CI) were calculated to assess its prognosis and metastasis in human cancer. A total of 1134 patients from 11 studies were included. The results indicated that overexpression of HULC was associated with poor overall survival (OS) (HR = 1.89, 95% CI: 1.32-2.47). Furthermore, subgroup analysis showed that cancer type (digestive system cancer or non-digestive system cancers) and sample size (more or less than 100) significantly associated between HULC and OS. In addition, overexpression of HULC expression was significantly associated with metastasis in cancers (HR = 2.67, 95% CI: 0.94-4.39). The meta-analysis indicated that lncRNA HULC could serve as a new molecular marker for cancer prognosis and metastasis.

How to detect the rare BCR-ABL (e14a3) transcript: A case report and literature review.

The Philadelphia (Ph; BCR-ABL) chromosome originates from a translocation event between chromosomes 9 and 22, and results in the BCR-ABL fusion gene. In chronic myelogenous leukemia (CML), the BCR-ABL gene is mainly coded for by a major breakpoint cluster region (M-bcr, e13a2 and e14a2). However, in some patients, BCR-ABL genes are encoded by a minor (m)-bcr, e1a2, and a micro (µ)-bcr region, e19a2. These transcripts revealed a different clinical course. The present study described a CML patient whose cytogenetics and FISH analyses of bone marrow revealed a karyotype of 46, XY t(9,22) (q34;q11), while the commercial kits of quantitative PCR (qPCR) failed to detect the BCR-ABL fusion gene. Further multiplex Reverse transcription-PCR (RT-PCR) and sequencing analyses identified a rare e14a3 (b3a3) fusion transcript.

Neutrophil CD64 Index as a superior biomarker for early diagnosis of infection in febrile patients in the hematology department.

BACKGROUND: In the hematology department, the availability of biomarkers for early detection of infection is difficult to obtain. The present study aimed to compare the diagnostic values of neutrophil CD64 Index, procalcitonin (PCT), interleukin-6 (IL-6) and C-reactive protein (CRP) and to determine whether the combined analysis of these biomarkers offer stronger predictive power in the diagnosis for the infection of febrile patients. METHODS: Neutrophil CD64 Index, PCT, IL-6 and CRP levels were determined in 356 febrile patients in the hematology ward from May 2013 to May 2015. Sensitivity, specificity, positive and negative likelihood ratios, positive and negative predictive values, receiver operating characteristic (ROC) areas under the curve (AUC), and logistic regression analysis were determined to evaluate the diagnostic values of these biomarkers. RESULTS: The levels of the four biomarkers were higher in the infection patients (p<0.001), and the PCT and IL-6 were higher in the patients with positive microbial blood culture (p<0.01). The neutrophil CD64 Index, PCT, IL-6, CRP had AUCs of 0.95, 0.83, 0.75 and 0.73, respectively. The best cut-off value of the neutrophil CD64 Index to detect infections was 5.06, with high specificity (87.5%) and sensitivity (88.4%). Furthermore, neutrophil CD64 Index, PCT and IL-6 offered the best combination of diagnosis with sensitivity of 93.9% and an AUC of 0.95. In addition, the neutrophil CD64 Index may have a special value to assist the physician to diagnose infection in the neutropenic patients with fever. CONCLUSIONS: The neutrophil CD64 Index is useful for early identification of infections in febrile patients in the hematology department. The combined analysis of the CD64 Index, PCT and IL-6 could further improve its sensitivity.

Relationship between JAK2V617F mutation, allele burden and coagulation function in Ph-negative myeloproliferative neoplasms.

OBJECTIVES: Our aim was to explore the relationship between JAK2V617F mutation allele burden and hematological parameters especially in coagulation function in Chinese population. METHODS: This study included 133 Ph-negative myeloproliferative neoplasms (MPNs) patients between 2013 and 2016. All the clinical and experimental data of patients were collected at the time of the diagnosis without any prior treatment, including blood parameters, coagulation function, splenomegaly, vascular events and chromosome karyotype. PCR and qPCR were used to detect JAK2V617F mutation and JAK2V617F mutation allele burden. RESULTS: In polycythemia vera patients, a positive correlation between the allele burden of JAK2V617F mutation and PLT counts was found; in essential thrombocythemia (ET) patients, WBC counts, RBC counts, HB, and HCT were higher in mutated patients than in wild-type patients. Furthermore, PT-INR was higher in ET and PMF mutated patients. In addition, a positive correlation between the allele burden of JAK2V617F mutation and activated partial thromboplastin time (APTT) was observed in JAK2V617F mutated ET patients. CONCLUSIONS: Higher hematologic parameters including counts of WBC, RBC, and PLT are closely associated with JAK2V617F mutation and its burden in Ph-negative MPNs; importantly, PT-INR, APTT are also related to JAK2V617F mutation and allele burden. Thus, our data indicate that JAK2V617F mutation allele burden might not only represent the burden of MPN but also alter the coagulation function.

Prognostic value of RDW in cancers: a systematic review and meta-analysis.

Red blood cell distribution width (RDW), a parameter that used to differentiate the type of anemia for several decades, recent studies suggest it was a prognostic factor in various types of cancer patients. However, the prognostic value of RDW in cancer patients remains controversial. Here, we performed a meta-analysis and systematic review to evaluate the prognostic value of RDW in cancer patients. Relevant studies were picked out from the databases of Web of Science, Embase, Pubmed and Cochrane Library. A total of 16 papers with 4267 patients were included in this meta-analysis, and the combined results indicated that elevated RDW was associated with poor over survival (OS) (HR = 1.47, 95%CI:1.29-1.66), poor cancer-specific survival (CSS) (HR = 1.46, 95%CI:1.08-1.85), poor disease-free survival (DFS) (HR = 1.91, 95%CI:1.27-2.56), poor event-free survival (EFS) (HR = 2.98, 95%CI:0.57-5.39) and poor progress-free survival (PFS) (HR = 3.21, 95%CI:0.33-6.75) after treatment. Furthermore, the similar results were observed in subgroup analysis stratified by cancer type, cutoff value of RDW, sample size and ethnicity. In conclusion, this meta-analysis demonstrated that RDW may be a potential prognostic marker in patients with cancer, and high RDW may also be associated with poor outcomes.

[The First Switched Time of PML/RARα Fusion Gene in Patients with Acute Promyelocytic Leukemia and Its Clinical Significance].

OBJECTIVE: To investigate the first switched time of PML/RARα fusion gene in patients with acute promyelocytic leukemia (APL) and its clinical significance. METHODS: sixty cases of newly diagnosed APL were enrolled in this study. They received standard remission induction, consolidation and maintenance treatments according to the clinical pathway for APL, and were followed up. During the same time the PML/RARα fusion gene mRNA expression of all cases was detected by multi-nested PCR. RESULTS: except for 3 death cases and 1 case failed to follow-up, the PML/RARα fusion genes in the remaining 56 cases were firstly found to be negative from 24 to 381 days respectively, the mean value of the first switched time was 131 ± 90 days. There was no statistically significant difference in age, sex and risk stratification between different groups. However, the cases with L-type PML/RARα gene had shorter time compared with the patients with S-type PML/RARα gene (P = 0.032); then, for the above-mentimed 56 cases, the follow-up duration ranged from 25-1979 days (median 946 days), long-term molecular remissions had been observed in most cases, but 1 case with the first switched time of 133 days unfortunately recurred to be positive and followed by clinical relapse. CONCLUSION: The PML/RARα fusion gene in newly diagnosed APL patients was first switched to be negative in about 4 months after treatment. The first switched time of PML/RARα fusion gene can objectively reflect the reduction of leukemia cells, and the differences among different subtypes of PML/RARα fusion gene may have some suggestions for the treatment, but without important significance for the evaluation of prognosis and recurrence for APL patients. In addition, minimal residual disease (MRD) can be dynamically monitored by detecting PML/RARα fusion gene, thus having an important clinical significance for analysis of APL recurrence.