Background:Hemophagocytic lymphohistiocytosis (HLH) is a fatal disorder characterized by uncontrolled inflammation. In adults, lymphoma is the most common underlying cause. The lipid profile is frequently dysregulated in lymphoma-associated HLH (LA-HLH), and the clinical significance remains to be determined. Objectives:This study aimed to evaluate the prognostic value of baseline lipid profiles and the dynamic changes in high-density lipoprotein cholesterol (HDL-c) in adult patients with LA-HLH. Design:A multicenter, retrospective cohort study. Methods:We analyzed 277 adult patients with LA-HLH from 27 medical centers (2015-2023). Baseline lipid levels and post-treatment HDL-c levels were measured. The optimal prognostic cutoff was determined using X-tile software. Survival analysis was performed using Kaplan-Meier and Cox regression methods. Results:Low HDL-c (<1.03 mmol/L) was observed in 93.9% (260/277) patients at diagnosis. A baseline HDL-c <0.48 mmol/L was independently associated with reduced overall survival (OS; hazard ratio, HR = 1.51, 95% confidence interval, CI: 1.10-2.09, p = 0.012) and 60-day survival (HR = 1.66, 95% CI: 1.10-2.49, p = 0.015). The post-treatment/baseline HDL-c ratio was significantly lower in patients with T/NK-cell malignancies than in those with B-cell non-Hodgkin lymphoma. A lower ratio (<1.71) was significantly associated with reduced survival. Patients with both low baseline HDL-c (<0.48 mmol/L) and low ratio (<1.71) constituted a high-risk group with the worst outcomes (60-day survival: 46.7% vs 81.8%, p = 0.004; median OS: 52 days vs not reached, p < 0.001). Conclusion:HDL-c and its dynamic changes are clinically feasible markers for predicting outcomes in patients with LA-HLH.

Birelentinib (DZD8586) is a LYN/BTK dual inhibitor designed to block both BTK-dependent and BTK-independent BCR signalling. In TAI-SHAN5 (NCT05824585) and TAI-SHAN8 (NCT06539182, CTR20240120) studies, patients who failed front line BTKi and/or BCL2i showed an overall response rate (ORR) of 84.2%. Similar responses were observed in patients with prior treatment of covalent BTKi, non-covalent BTKi as well as BTK degraders, with BTK C481X or “kinase-impaired” mutations (ASCO 2025). Here we report follow-up results of these studies. The data from TAI-SHAN5 and TAI-SHAN8 studies were pooled for the efficacy and safety analysis. Tumor response was assessed by investigators per iwCLL 2018 or Lugano 2014 criteria, as appropriate. All enrolled patients were included in safety analysis, and those patients enrolled by January 2025 were included in efficacy analysis to assess efficacy with long-term follow-up. As of July 7, 2025, a total of 65 patients with r/r CLL/SLL have been enrolled and received DZD8586 at doses ranging from 25 mg to 100 mg once daily (QD). At the recommended phase 3 dose (RP3D), 50 mg QD, 44 patients were enrolled. The median age was 62.5 years, 68% were male, and 64% had ECOG score of 1 or 2. The median number of prior therapies was 2 (range 1-5). Del(17p) and/or TP53 mutation was detected in 37% of the patients. Prior therapies included BTK inhibitor (71%, including 7% treated with non-covalent BTK inhibitor and 5% treated with BTK degrader), BCL-2 inhibitor (23%), and chemoimmunotherapy (41%). BTK mutations were detected in 55% of patients, including kinase proficient BTK mutation (55%) and kinase impaired BTK mutation (32%). In the efficacy analysis set at RP3D (N=19), 16 out of 19 patients achieved tumor response, with overall response rate (ORR) of 84.2%. Tumor response was observed in patients who received prior treatment with BTK inhibitors (ORR 82.4%, including non-covalent BTK inhibitors [2/2, ORR 100%]), Bcl-2 inhibitor (5/6, ORR 83%), and BTK degrader (1/2, ORR 50%). With median follow-up of 8.3 months, the estimated 12-month PFS rate was 61.9%. As of data cut-off date, the longest responder was on therapy for 12.1 months. DZD8586 was well tolerated across the doses investigated. No new safety signals were identified. At the RP3D, the most common ≥grade 3 drug-related TEAEs were neutropenia (22.7%). No febrile neutropenia was reported. No major bleeding or atrial fibrillation was reported. Nine percent of the patients had drug-related TEAEs leading to dose reduction. Only one patient discontinued treatment due to drug-related TEAE (cough). No drug-related TEAE related death was reported. DZD8586 showed encouraging anti-tumor activity with well tolerated and manageable safety profile in heavily pre-treated CLL/SLL patients, including patients with prior covalent BTKi, non-covalent BTKi, BTK degrader, and Bcl-2 inhibitor treatment. Durable tumor response was observed. The updated data will be presented at the meeting.

7010 Background: New therapies are needed for patients with relapsed or refractory (r/r) CLL/SLL following covalent and/or non-covalent BTK inhibitors. While early clinical data showed encouraging anti-tumor activities from BTK degraders in these patients, resistance mutations to both BTK inhibitors and degraders have already been reported. In addition, concerns with emerging clinical safety signals from these degraders may limit their longer-term clinical use. DZD8586 is a rationally designed LYN/BTK dual inhibitor with high selectivity against other TEC family members. Here we report results from ongoing phase 1/2 clinical studies of DZD8586 in r/r CLL/SLL patients with prior treatment of covalent and/or non-covalent BTK inhibitors as well as BTK degraders. Methods: The data from two clinical studies, TAI-SHAN5 (NCT05824585) and TAI-SHAN8 (NCT06539182, CTR20240120), were pooled for the safety and efficacy analysis in patients with CLL/SLL. Modulation of PD biomarkers was evaluated at doses tested. Tumor response was assessed by investigators per iwCLL 2018 or Lugano 2014 criteria as appropriate. Results: As of January 3, 2025, a total of 40 patients with r/r CLL/SLL have been enrolled and received DZD8586 at doses ranging from 25 mg to 100 mg once daily (QD). The median age was 64.5 years, 62.5% were male, and 60% had ECOG score of 1 or 2. A total of 30 patients were evaluable for efficacy analysis. The median number of prior therapies was 2 (range 1-8). Most common prior CLL/SLL therapies included BTK inhibitor (76.7%), and Bcl-2 inhibitor (43.3%). Patients previously treated by non-covalent BTK inhibitor (13.3%) and BTK degrader (13.3%) were also reported. Across all dose levels, 15 out of 30 patients achieved tumor response, with objective response rate (ORR) of 50%. At the recommended phase 2 dose (RP2D) of 50 mg QD, 9 out of 14 patients achieved tumor response, with ORR of 64.3%. Efficacy was observed in patients with prior BTK inhibitor treatment (ORR 52.2%), and Bcl-2 inhibitor treatment (ORR 46.2%). Seventy five percent patients who received prior BTK degrader treatment achieved partial response. As of the data cut-off date, the longest responder was on therapy for 12.1 months. Deepening response was observed with longer treatment time. DZD8586 was well tolerated across the doses investigated. At the RP2D, the most common ≥grade 3 TEAEs were neutropenia (15%) and pneumonia (10%). No major bleeding or atrial fibrillation was reported. No grade 4/5 AEs reported. Conclusions: DZD8586 showed encouraging anti-tumor activity with a well tolerated and manageable safety profile in heavily pre-treated CLL/SLL patients, including patients with prior covalent BTKi, non-covalent BTKi, BTK degrader and Bcl-2 inhibitor treatment. PK/PD results confirmed dose/exposure-dependent pathway inhibition by DZD8586. The updated data will be presented at the meeting. Clinical trial information: NCT06539182 , NCT05824585 .

Lymphoma-associated hemophagocytic lymphohistiocytosis (LA-HLH) is a life-threatening hyperinflammatory syndrome, and hierarchical management based on a prognostic model is important. The endothelial activation and stress index (EASIX) score has demonstrated prognostic utility in recipients of allogeneic stem cell transplantation and chimeric antigen receptor (CAR) T-cell therapy. However, its role in LA-HLH remains unestablished. We conducted a multicenter retrospective analysis of patients with LA-HLH from 28 medical centers to explore the prognostic impacts of EASIX in LA-HLH. EASIX was calculated using baseline lactate dehydrogenase, serum creatinine, and platelet counts. A total of 490 patients with LA-HLH were included and stratified by EASIX quartiles (Q1-Q4). Patients with a higher EASIX score had significantly inferior 2-month survival and overall survival, according to the Kaplan-Meier analysis (log-rank p < 0.001). In multivariable analyses, after adjustment for age, gender, lymphoma type, splenomegaly, bone marrow infiltration, lymphoma status (treatment-naïve versus relapsed/refractory), hemoglobin, absolute neutrophil count, serum ferritin levels, and aspartate aminotransferase, the highest EASIX quartile (Q4) exhibited a 7.01-fold risk of death compared to the lowest quartile (Q1) (Hazard ratio [HR] = 7.01, 95% confidence interval [CI]: 3.98-12.36; p < 0.001). Additionally, the restricted cubic splines (RCS) analysis illustrated an increase in the risk of mortality with an increasing EASIX score. Our findings support EASIX being a robust, universally accessible prognostic marker for LA-HLH, strongly associated with early mortality risk. This index can be used to stratify the risk levels of patients with LA-HLH and predict their survival outcomes.

OBJECTIVE:To explore the impact of age on the genetic variant spectrum and prognosis of patients with previously untreated Diffuse large B-cell lymphoma (DLBCL). METHODS:A retrospective analysis was conducted on the clinical data and follow-up information of 254 previously untreated DLBCL patients from 14 hospitals in the Jiangsu Cooperative Lymphoma Group (JCLG) enrolled from July 2018 and July 2023. Following extraction of DNA from tumor tissue samples, next-generation sequencing (NGS) technique was employed to analyze the genetic variant spectrum of the DLBCL patients, with an evaluation of the relationship between age and genetic variants as well as prognosis. This study was approved by the Medical Ethics Committee of the Affiliated Hospital of Nantong University (Ethics No.: 2023-K048-01). RESULTS:The median age of the 254 DLBCL patients was 62 years old, with 55% of patients aged 60 years or above. Clinical evaluation showed that younger (< 60 years) patients had higher complete response (CR) (70% vs. 59%), and objective response rate (ORR) (88% vs. 79%) than older patients, though the difference between the two groups was not statistically. Survival analysis indicated that both the five-year overall survival (OS) (82.7% vs. 71.7%, P = 0.006) and progression-free survival (PFS) (70.6% vs. 50.2%, P < 0.05) rates were significantly higher in younger patients. NGS showed that 99.6% of the patients harbored genetic variants, with PIM1, KMT2D, TP53, MYD88, and CD79B being the most common genes. Age significantly affected the variant frequency of certain genes, with MYC variants serving an adverse prognostic factor for OS in younger patients (P = 0.002), while TP53 (P = 0.024) and BCL2 (P = 0.002) variants significantly impacted OS in older patients. Prognostic analysis identified age ≥ 60 years (HR = 3.439, 95%CI: 1.318~9.874), presence of B symptoms (HR = 2.871, 95%CI = 1.133~7.307), and elevated lactate dehydrogenase (HR = 3.528, 95%CI = 1.231~10.66) as independent adverse prognostic factors. CONCLUSION:Age, genetic variants, and clinical factors may significantly affect the prognosis of the DLBCL patients. Younger patients have better survival compared to older patients. Variants of the MYC, BCL2, and TP53 genes are closely associated with poor prognosis.

Introduction: Lymphoma is the most common underlying cause of secondary hemophagocytic lymphohistiocytosis (HLH). In Asian countries, T or NK-cell lymphoma-associated HLH (T/NK-LAHLH) is more common than B-cell lymphoma-associated HLH. There are no established prognostic markers for T/NK-LAHLH. Endothelial Activation and Stress Index (EASIX) is a marker of endothelial activation and could predict mortality in patients treated with allogeneic stem cell transplantation. Whether EASIX could predict survival in T/NK-LAHLH remains to be determined. Materials and Methods: Patients with T/NK-LAHLH were included. EASIX was calculated by the formula: lactate dehydrogenase (U/L)×creatinine (mg/dL)/thrombocytes (10⁹ cells per L). The diagnosis of HLH was based on the HLH-2004 criteria. Only patients with a histological diagnosis and follow-up were included. The subtyping was based on the 2016 World Health Organization classification of lymphoid neoplasms. X-tile was used to determine the best cutoff of EASIX for survival prediction. Results: A total of 212 cases of T/NK-LAHLH were identified. The most common subtype of T/NK cell malignancy was extranodal NK/T cell lymphoma, nasal type (57, 26.9%) followed by aggressive NK cell leukemia (55, 25.9%) and peripheral T cell lymphoma, not otherwise specified (29, 13.7%). The best cutoff of EASIX for predicting 60-day survival was 40.1. Patients with high EASIX values (>40.1) had a significantly poorer 60-day survival than those with low EASIX values (≤40.1) (60-day survival rate: 15.6% vs. 63.9%, p<0.0001). Patients with high EASIX also showed significantly poorer overall survival (median survival: 14 days vs. 79 days, p<0.0001). For patients with NK cell malignancies, a higher EASIX also significantly predicted a reduced 60-day survival rate (p<0.0001) and overall survival (p<0.0001). Patients with high EASIX values showed significantly lower levels of hemoglobin, neutrophil count, albumin, and fibrinogen and higher levels of aspartate aminotransferase, alanine aminotransferase, and triacylglycerol (p values all < 0.05). EASIX>40.1 (hazards ratio[HR] 3.60, 95%CI: 2.31-5.60; p<0.0001), fibrinogen≤1.5g/L (HR 1.67, 95%CI: 1.07-2.58; p=0.023), and age>60 (HR 1.76, 95%CI:1.14-2.71; p=0.011) were identified as independent predictors of worse 60-day survival in multivariate analysis. A prognostic index was established by combining these three independent predictors. We assigned a weighted score of 1 to fibrinogen and age, and 2 to EASIX. Finally, a prognostic index for T/NK-LAHLH (T/NK-LAHLH-PI) ranged from 0 to 5 was established (T/NK-LAHLH-PI: low-risk 1, intermediate-risk 2, high-risk ≥2). T/NK-LAHLH-PI significantly predicted different 60-day survival rates (low-risk 77.3% vs. intermediate-risk 50.1% vs. high-risk 24.9%, p<0.0001) and overall survival (median survival: low-risk 340 days vs. intermediate-risk 63 days vs. high-risk 20 days, p<0.0001). Conclusions: Our study demonstrated that EASIX was a robust marker for predicting outcomes in patients with T/NK-LAHLH. T/NK-LAHLH-PI, a prognostic index containing EASIX, could be used to predict the outcomes of patients with T/NK-LAHLH.

Background: Lymphoma is the most common secondary cause of hemophagocytic lymphohistiocytosis (HLH) in adults. Lymphoma-associated HLH (LA-HLH) in the elderly population is not rare, however, little has been reported regarding clinicopathological characteristics, prognostic factors, and outcomes of LA-HLH in the elderly population. Methods: We retrospectively analyzed a multicenter cohort of elderly patients with LA-HLH. Clinicopathological features and treatment information were collected. The impacts of baseline characteristics and treatments on survival outcomes were analyzed. Results: A total of 173 elderly patients with LA-HLH were included. Compared with young patients, elderly patients showed different clinical and laboratory features. Regarding lymphoma subtypes, B-cell lymphoma was more common in elderly patients (elderly 61.3% vs. young 32.3%, p < 0.001) while T/NK-cell lymphoma was more common in young patients (65.3% vs. 35.3%, p < 0.001). The median survival of elderly patients with LA-HLH was only 92 days. The prior use of HLH therapy or etoposide-containing HLH therapy was not associated with improved overall survival. T/NK-cell subtype, a lower platelet count (<= 53 x 10(9)/L), a lower albumin level (<= 32.1 g/L), a higher LDH level (>1407 U/L), and a higher creatinine level (>96.8 mu mol/L) were independent predictors of decreased overall survival and 60-day survival. A prognostic index was established and demonstrated to be robust in predicting the overall survival and 60-day survival of elderly patients with LA-HLH. Conclusions: LA-HLH in elderly patients displayed heterogeneous clinicopathological features and survival outcomes. Treatments need to be optimized to improve the outcomes of elderly patients with LA-HLH.

Introduction: Lymphoma is the most common underlying cause of secondary hemophagocytic lymphohistiocytosis (HLH). The detailed pathological subtypes of lymphomas presenting with HLH remain less well-defined. The prognostic role of pathological subtypes in patients with lymphoma-associated HLH (LA-HLH) has not been studied in a large cohort. Survival trends of patients with LA-HLH has not been explored. Whether the advent of novel therapies and better supportive care improves the outcomes of patients with LA-HLH remains to be determined. Methods: Patients with LA-HLH were included. The diagnosis of HLH was established according to the HLH-2004 criteria. Only patients with a histological diagnosis and follow-up were included. The subtyping was based on the 2016 World Health Organization classification of lymphoid neoplasms. Results: A total of 464 cases of LA-HLH were included in this study. Two-hundred and twenty-six cases were diagnosed from 2010-2019 (Era 1) and 238 patients were diagnosed from 2020-2024 (Era 2). Two-hundred and forty-three cases were T/NK cell lymphoma (52.4%), 206 B cell lymphoma (44.3%), 12 Hodgkin lymphoma (HL, 2.6%), and 3 composite lymphoma (0.6%). The most common lymphoma subtypes included large B cell lymphoma (LBCL, n=190, 40.9%), aggressive NK cell leukemia (ANKL, n=66, 14.2%), extranodal NK/T cell lymphoma, nasal type (n=64, 13.8%), peripheral T cell lymphoma, not otherwise specified (n=28, 6.0%), and angioimmunoblastic T cell lymphoma (n=28, 6.0%). Patients with B cell LA-HLH had better outcomes than those with T/NK cell LA-HLH (median survival: 418 days vs. 72 days, p<0.0001; 60-day survival: 68.8% vs. 53.4%, p=0.0012). For specific subtypes, patients with ANKL-associated HLH showed the worst outcome with a median survival of only 39 days (60-day survival: 43.7%). Patients with LBCL-associated HLH had a median survival of 420 days. Survival of B cell LA-HLH improved remarkably in recent years (median survival: 238 days in Era 1 vs. Undefined in Era 2, p=0.0019; 60-day survival: 61.8% in Era 1 vs. 74.2% in Era 2, p=0.0441). The survival of T/NK cell LA-HLH also improved (median survival: 54 days in Era 1 vs. 97 days in Era 2, p=0.0177; 60-day survival: 47.3% in Era 1 vs. 60.5% in Era 2, p=0.0402). The outcomes for patients with NK cell LA-HLH also improved in recent years (median survival: 39 days in Era 1 vs. 105 days in Era 2, p=0.0171; 60-day survival:40.6% in Era 1 vs. 66.4% in Era 2, p=0.0074). Conclusions: To our knowledge, we presented the largest cohort of LA-HLH. T/NK cell LA-HLH is more common than B cell LA-HLH in China. The most common lymphoma subtypes related to HLH included LBCL, ANKL, and ENKL. The pathological subtypes had significant impacts on the survival outcomes of patients with LA-HLH. Patients with T/NK cell LA-HLH had poorer outcomes, especially those with ANKL. The survival of both B cell LA-HLH and T/NK cell LA-HLH improved recently, probably due to novel agents and better supportive care.

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome characterized by an excessive immune response. Beta-2 microglobulin (B2M) forms the light chain section of the major histocompatibility complex (MHC) class Ⅰ antigen. The prognostic role of B2M in lymphoma-associated HLH remains to be determined. This study was to investigate the prognostic role of serum B2M in adult lymphoma-associated hemophagocytic lymphohistiocytosis (HLH). Methods: The clinical and laboratory characteristics of adult patients in a multicenter cohort with lymphoma-associated HLH who had baseline serum B2M levels between August 2009 and June 2023 were retrospectively analyzed. The diagnosis of HLH was established according to the HLH-2004 criteria. Results: A total of 326 cases were included and the median serum B2M level was 5.19 mg/L. The most common subtype of lymphoma was T/NK cell lymphoma (51.8%, 169/326), followed by B-cell non-Hodgkin lymphoma (45.4%, 148/227) and Hodgkin lymphoma 8/326 (2.5). The optimal cut-off value of serum B2M for predicting overall survival was 8.73 mg/L (p < 0.0001). Patients were divided into two subgroups by the optimal cut-off value. The median survival was 21 days for the high level subgroup, and 236 days for the low level subgroup (Figure 1). The 6-month survival rates were 22% and 54%, respectively. The subgroup with B2M level > 8.73 mg/L was older and had a higher proportion of stage IV. Patients with higher levels of B2M showed lower levels of platelets, albumin, and fibrinogen, and high levels of creatinine. A moderate correlation between creatinine and serum B2M was found (Spearman's ρ = 0.417, p < 0.001). The multivariate analysis showed that the high levels of serum B2M (> 8.73 mg/L) and creatinine (≥ 133 μmol/L), decreased fibrinogen (≤ 1.5 g/L), agranulocytosis (< 0.5×10 9/L), severe thrombocytopenia (< 50×10 9/L), and increased Epstein-Barr virus DNA were found to have significant prognostic values in all patients. The high serum B2M level (> 8.73 mg/L), severe thrombocytopenia (< 50×10 9/L), agranulocytosis (< 0.5×10 9/L), and high Epstein-Barr virus DNA copy number were independent prognostic factors in patients with creatinine < 133 μmol/L. Finally, a prognostic scoring system was established based on serum B2M levels as well as five other independent prognostic factors and divided the patients into three groups with significant prognostic differences (median survival: low-risk [score ≤ 1] 428 days vs. intermediate-risk [score = 2] 102 days vs. high-risk [score ≥ 3] 18 days, P < 0.0001) (Figure 2). The 6-month survival rates were 67%, 46% and 14%, respectively. Conclusions: This study confirmed that the serum B2M level could be an independent prognostic factor in lymphoma-associated HLH and established a prognostic scoring system to predict patients' survival.

KMT2A (Lysine methyltransferase 2A), also known as MLL (Mixed Lineage Leukemia), is rearranged in 5% of de novo adult acute myeloid leukemia (AML), 24% of pediatric AML, 60%–70% of infant acute lymphocytic leukemia (ALL), and 10% of adult ALL. However, KMT2A rearrangement is rare in myelodysplastic syndromes and has never been reported in chronic neutrophilic leukemia (CNL). KMT2A is genetically promiscuous and has more than 100 fusion partner genes reported so far. In this study, we identified a novel fusion partner of KMT2A, dipeptidyl carboxypeptidase 1B (DCP1B), in a patient with classic CNL. To our knowledge, this is the first reported KMT2A rearrangement in CNL. Additionally, we have discovered four previously unpublished DCP1B rearrangements in cancer through our search of the Cancer Genome Atlas (TCGA) database. We further discussed the crucial role of DCP1B, which is a critical enzyme involved in mRNA turnover, in oncogenesis. A 69-year-old female patient presented with leukocytosis and no tumor history. A physical examination showed no signs of lymphadenopathy, hepatosplenomegaly, or bruising. Complete blood counts showed a white blood count of 61.17 × 109/L, a hemoglobin level of 116 g/L, a platelet count of 201 × 109/L, and differential counts of 90% neutrophils, 3% myelocytes and metamyelocytes, 5% lymphocytes, 2% monocytes, 0% eosinophils, and 0% basophils (Figure 1A). The bone marrow aspirate smear indicated that 85% of cells were myeloid elements, mainly comprising myelocyte to segmented forms. Neutrophils showed varying degrees of toxic granulation, but no signs of neutrophil dysplasia were observed (see Figure 1B). Furthermore, there was no evidence of blasts, erythroid dysplasia, or megakaryocytic dysplasia. A bone marrow biopsy showed a hypercellular marrow (>90% cellularity) with neutrophilic proliferation, normal myeloid maturation, and slightly increased erythroid and megakaryocytic elements with no dysplasia. Mild bone marrow fibrosis was noted in some areas (grade 1 according to European consensus). Flow cytometry of the bone marrow aspirates showed no significant immunophenotypic abnormalities. Cytogenetic analysis showed translocation of chromosomes 11 and 12 as the sole change, 46,XX,t(11;12)(q23; p13)[7]/46,XX [13] (Figure 1C). Fluorescence in situ hybridization (FISH) using a KMT2A split-apart probe showed KMT2A rearrangement, with the 3′ KMT2A translocated to chromosome 12p (Figure 1D). The FISH assay showed 12.5% of interphase nuclei with the KMT2A rearrangement. Targeted DNA next-generation sequencing (NGS) showed CSF3R c.1853 C>T p. Thr618Ile (VAF 38.4%) and SRSF2 c.281_283dupGCC p. Arg94dup (44.3%). The gene copy number evaluation revealed a balanced genome, consistent with the karyotype results. Based on the defining CSF3R mutation and the classic morphologic features, the diagnosis of CNL was made. The patient has been treated with hydroxyurea and remains in stable condition. To identify the fusion partner of KMT2A, we performed targeted RNA NGS, which revealed a fusion transcript of KMT2A::DCP1B. The first eight exons (exons 1–8) of KMT2A were fused to the final three exons (exons 6–9) of DCP1B (Figure 2A). An RT-PCR assay was performed with primers specific for KMT2A (F_KMT2A E8:5′-TCCAGAGCAGAGCAAACAGA) and DCP1B (R_DCP1B E6: 5′-AGATGGCAGAGGAACTGGTT), which obtained a PCR product at the expected size. Sanger sequencing confirmed the KMT2A::DCP1B fusion (Figure 2B). The predicted fusion protein comprises the menin-binding domain (MBM), the LEGDF binding domain (LBD), and the zinc finger-CxxC (CXXC) domain of the KMT2A protein, as well as the trimerization domain (TD) of the DCP1B (Figure 2A). We searched the TCGA database to investigate DCP1B rearrangement in other tumors and identified four additional DCP1B fusions with intact reading frames that have not been previously reported. These include (1) a SCNN1A::DCP1B fusion in a 75-year-old male with squamous cell carcinoma of the tongue, which comprises the association with the SNF1 complex (ASC) domain of SCNN1A (α subunit of the epithelial sodium channel ENaC) and partial TD domain of DCP1B. Two fusion transcripts were identified, which are likely products of differential splicing; (2) an ADIPOR2::DCP1B fusion in a 71-year-old male with transitional cell carcinoma of the bladder, which comprises the Enabled/VASP Homology-1 (EVH1) domain of ADIPOR2 (Adiponectin Receptor 2) and the TD domain of DCP1B; (3) a FOXM1::DCP1B fusion in a 57-year-old female with gastric adenocarcinoma, which comprises the Forkhead domain of FOXM1 (Forkhead box protein M1) and TD domain of DCP1B; and (4) an ANO2::DCP1B fusion in a 45-year-old female with serous ovarian cancer, which comprises Anoct dimer domain and EVH1 domain of ANO2 (Anoctamin 2) and TD domain of DCP1B. Figure 2C shows the schematic of the DCP1B fusion proteins. KMT2A is an essential histone methyltransferase that regulates gene expression, DNA damage response, and hematopoietic stem cell (HSC) differentiation.1 The SET domain of the KMT2A is responsible for chromatin modifications associated with epigenetic transcriptional activation, including genes critical for normal development, such as Hox genes.2 KMT2A is involved in recruiting DNA repair factors, including ATM, ATR, and BRAC1, to DNA damage sites, and regulating gene expression in response to DNA damage.3 Cells with impaired KMT2A function have reduced DNA damage response and increased susceptibility to DNA damage-induced cell death.4 KMT2A regulates HSC self-renewal and differentiation, and its loss results in reduced production of various blood cell types. Conversely, overexpression of KMT2A can lead to an HSC population expansion.5 KMT2A is frequently rearranged in leukemia, with more than 100 different partner genes identified. The specific partner gene involved in a given KMT2A rearrangement can have important implications for the clinical outcome of the associated leukemia, as well as for the underlying molecular mechanisms of the disease.6, 7 DCP1B is the latest member of the KMT2A fusion partner family. DCP1 is a de-capping enzyme that removes the 5′ m(7)G cap from mRNA and plays a critical role in mRNA decay in eukaryotic cells.8 DCP1A and DCP1B are two closely related isoforms that likely function redundantly.8 DCP1A has been observed to be overexpressed in several types of cancer, including colorectal cancer, gastric cancer, melanoma, and hepatocellular carcinoma. In some cases, high levels of DCP1A have been associated with poor prognosis and reduced survival.9 KMT2A::DCP1B and other DCP1B fusion proteins as shown in Figure 2C contain the TD of DCP1B, which mediates interactions between three DCP1B molecules and is also responsible for the proper assembly of the proteasome.8 The oncogenic mechanism of KMT2A::DCP1B is yet to be established, but it may affect mRNA metabolism of critical oncogenes or tumor suppressors by interacting with the wild-type DCP1B via the TD domain.10 Alternatively, KMT2A::DCP1B could affect KMT2A-related cellular functions by binding to other proteins. Although ASXL1, TET2, and DNMT3A, which are involved in epigenetic regulation, are mutated in CNL, this is the first reported case of KMT2A rearrangement in CNL. Because the KMT2A rearrangement was detected in only 12.5% of cells, whereas the VAF of CSF3R c.1853 C>T p.Thr618Ile was 38.4% in the same specimen, it is likely that the KMT2A rearrangement is present in a subclone and represents a later event during disease progression. Consequently, even though the 5th edition of the WHO classification of hematolymphoid tumors suggests diagnosing AML with a KMT2A rearrangement without requiring 20% or more blasts, we do not classify this as AML. Instead, it is more appropriately categorized as a CNL with a KMT2A rearrangement. The actual effect of KMT2A::DCP1B on disease progression is currently unknown. The prognosis of KMT2A-rearranged leukemia is generally poor, but that target the KMT2A-menin interaction have shown promising effects in treating patients.11 In summary, we present the first documented KMT2A rearrangement in CNL and first documented DCP1B rearrangements in tumor. Recurrent DCP1B involvement in a variety of tumors may help understand its role in tumorigenesis and serve as a potential biomarker for future therapeutic targets. This work was supported by research funds from the National Natural Science Foundation of China (81300382); Wuxi Medical Development Discipline (FZXK2021005), Wuxi Young Medical Talents (QNRC074), the Scientific research project of Wuxi Health Committee (M202138). The authors declare no conflicts of interest. Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Cryptotanshinone (CT) is an extract from the traditional Chinese medicine Salvia miltiorrhiza , which inhibits the growth of methicillin-resistant Staphylococcus aureus (MRSA) in vitro. This study aims to determine the antibacterial mechanisms of CT by integrating bioinformatics analysis and microbiology assay. The microarray data of GSE13203 was retrieved from the Gene Expression Omnibus (GEO) database to screen the differentially expressed genes (DEGs) of S. aureus strains that were treated with CT treatment. Gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were used to identify the potential target of CT. Data mining on the microarray dataset indicated that pyruvate kinase (PK) might be involved in the antimicrobial activities of CT. The minimum inhibition concentrations (MICs) of CT or vancomycin against the MRSA strain ATCC43300 and seven other clinical strains were determined using the broth dilution method. The effects of CT on the activity of PK were further measured. In vitro tests verified that CT inhibited the growth of an MRSA reference strain and seven other clinical strains. CT hampered the activity of the PK of ATCC43300 and five clinical MRSA strains. CT might hinder bacterial energy metabolism by inhibiting the activity of PK.

Purpose: To identify the biological function of phosphoserine aminotransferase 1 (PSAT1) in regulating cell proliferation and apoptosis in multiple myeloma (MM).Methods: The mRNA and protein levels of PSAT1 were determined using quantitative real-time polymerase chain reaction (PCR) and western blotting, respectively. Cell proliferation was measured using CCK-8 assay.Results: PSAT1 mRNA and protein expression levels were significantly increased in MM cell lines when compared to control cells. Moreover, downregulation of PSAT1 inhibited MM cell proliferation and induced cell apoptosis, whereas overexpression of PSAT1 promoted MM cell proliferation and suppressed cell apoptosis. Further analysis demonstrated that the underlying mechanism was via regulation of PI3K/AKT pathway.Conclusion: The results identified a novel role for PSAT1 in the progression of MM, which may provide a therapeutic and a new anticancer target for the therapy of MM. Keywords: Multiple myeloma, PSAT1, Cell proliferation, PI3K/AKT pathway

In this study, we have developed a method to quantify inherent conditioner-to-conditioner variation using a mathematical model. Quantification of the lifetime of pad and conditioner in a chemical mechanical planarization (CMP) process using the model is also elucidated. Three conditioner types are selected based on their aggressiveness, and conditioning experiments are performed with five different conditioners of the same type to quantify the variation. Assuming exponential decay equation for pad wear rate (PWR), a simple model is developed and the model parameters, K and λ, are derived in numeric form. K, a measure of conditioner aggressiveness, can be used as a metric to assess conditioner-to-conditioner variation, while λ is a measure of conditioner lifetime. K and λ values are also used to predict the failure mode of a CMP process (conditioner or pad failure mode). Pad groove depth and PWR curves of five different conditioners of the same type as a function of time are plotted along with upper and lower limits. The limiting factor (low PWR due to conditioner decay or excess pad removal) is identified to predict the failure mode. An example for each failure mode (A122 and 8031C1 conditioners for conditioner and pad failure modes, respectively) is presented.

OBJECTIVE:To investigate the effects of oridonin (ORI) on the proliferation and apoptosis of human multiple myeloma cell line H929 and its possible mechanism.METHODS:H929 cells were exposed to ORI 0、4、8、12、16、20、24、28、32 μmol/L for 12, 24 and 36 hours respectively. The prolifcration inhibitory effect of ORI on H929 cells was determined by MTT assay and then the working concentrations of ORI were determined. The morphological changes and apoptosis of H929 cells were observed by TUNEL (TdT-mediated dUTP Nick-End Labeling) and fluorescence microscopy. The apoptosis rate of H929 cells was detected by flow cytometry with Annexin V-FITC/PI staining. The protein expressions of pro-caspase-3, BCL-2，p-PI3K, p-Akt, BAX, Cleaved PARP and p-JNK, p-ERK and p-p38 in H929 cells were detected by Western blot.RESULTS:Compared with the control group, the proliferation of H929 cells treated with the ORI of 8-16 μmol/L was significantly inhibited and the apoptosis of H929 cells was obviously increased in dose- and time-dependent manners. As for morphological changes, the characteristics of apoptotic cells were presented in H929 cells treated with ORI for 24 hours. The protein levels of pro-caspase-3, BCL-2，p-PI3K, p-Akt were down-regulated with increasing of ORI concentration（r=0.9861, r=0.9725, r=0.9413, r=0.9373）, while the BAX, Cleaved PARP and p-JNK, p-ERK and p-p38 were up-regulated（r=0.9178, r=0.8877, r=0.882, r=0.9645, r=0.8623）.CONCLUSION:The ORI possesses anti-myeloma effects, can inhibit the proliferation and induce the apoptosis of H929 cell line in vitro. Its potential mechanism may be related with up-regulating the MAPK and down-regulating the PI3K/Akt signal pathways.

Background: Acute promyelocytic leukaemia (APL) is a special subtype of acute myeloid leukaemia. The aim of this study was to investigate the anti-tumour effects of puerariae radix flavones (PRF), the total flavonoids from Chinese herb puerariae radix (PR), on the human APL cell line NB4 and to explore the potential mechanisms. Methods: NB4 cells were exposed to various concentrations (0, 10, 30, 50 μg/ml) of PRF. Cell viability was measured by MTT assay. The cell cycle, the extent of cell apoptosis and the mitochondrial transmembrane potential were analysed with flow cytometry (FCM). The expression of apoptosis-related proteins was assayed by western blot. Results: We found that PRF inhibited cell viability of NB4 cells in a timeand dose-dependent manner. The cell cycle was arrested in the G0/G1 phase. FCM assays showed that PRF induced apoptosis and decreased mitochondrial membrane potential in a dose-dependent manner. NB4 cells treated with PRF expressed higher levels of cleaved caspase-3, caspase-9 and poly ADP-ribose polymerase (PARP) with an increased Bax/Bcl-2 ratio and Bcl-xL expression. Western blot analysis showed that expression of JNK was significantly lower while the expression of p-JNK was greater. Further analysis showed activation of the JNK pathway of NB4 cells by PRF. Conclusions: Our data, taken together, indicate that PRF exerted a potent anti-tumour effect on NB4 cells by inducing apoptosis, the mechanism of which might be accompanied with the JNK pathway and the mitochondrial pathway activation.

The Stribeck+ curve was successfully applied to silicon dioxide chemical mechanical planarization processes to characterize the tribology of such processes under different process conditions and consumables. Results showed that the Stribeck+ curve was capable of rapidly determining and differentiating the tribological mechanism among all cases studied in this manuscript. The Stribeck+ curve could indicate process stability as shown by the spread of the COF vertical clusters. The Stribeck+ curve also confirmed a previously known effect that the greater the ratio of pad's up-features to the total pad area, the greater the probability of wafer hydroplaning. This work underscore the importance of a new method for determining an "improved" Stribeck curve ( referred as the "Stribeck+ curve") while dramatically reducing the amount of consumables and time required to obtain the curve through traditional means. (c) 2017 The Electrochemical Society. All rights reserved.

Objective:To investigate the clinical effect of second-generation tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia ( CML) . Methods:A total of 64 patients with CML treated between January 2013 and December 2016 were selected as study subjects and treated with second-generation tyrosinekinase inhibitor ( TKI) . Among them,there were 41 cases treated with Nilotinib and 23 cases with Dasatinib. In patients treated by TKI,there were 13 cases receiving first-line medication and 51 cases receiving second-line medication. All were followed up for 6 ~ 54 months,median 18 months. The overall complete hematologic remission ( CHR) rate,CCyR rate,rate of major cytogenetic response ( MCyR),MMR rate,follow-up over-all survival rate ( OS) and event free survival rate ( EFS) were observed;Meanwhile,the responses of first-line and second-line treatment and adverse drug reactions were compared. Results:At the end of follow-up,43 cases continued second-generation TKI treatment, 14 cases died, 2 cases stopped medication, 2 cases were lost to follow up and 3 cases changed the medication regimen;In terms of overall responses to treatment,the rates of CHR, MCyR, CCyR and MMR were 98. 44%, 64. 00%, 59. 37% and 43. 75% respectively; In terms of overall survival status,OS and EFS decreased with duration of the disease. The rates of CCyR,MCyR and MMR of first-line treatment were significantly higher than the second-line treatment ( P < 0.05);There were no significant differences in the incidence of adverse drug reactions between Nilotinib and Dasatinib ( P >0.05) . Conclusion:The effect of Nilotinib and Dasatinib second-generation TKI in the treatment of CML is clear. The prognosis is good and safety is better; The effect of second generation TKI first-line treatment is better than second-line treatment in treating CML.

Objective To systematically assess the effectiveness and safety of subcutaneous bortezomibin comparison with intravenous bortezomib for treating multiple myeloma.Methods Data from relative clinical trials were from Clinicaltrials.gov and Cochrane Collaboration.A comprehensive literature search was performed from data bases such as PubMed and EmBase.The data of effective and safety on subcutaneous and intravenous administration was comparison.The Meta analyzed by RevMan5.3 Software.Results Three randomized controlled trials (RCT) and 8 retrospective cohort studies(RCS),11 research papers in total met inclusion criteria,including 2021 cases.There were no significant differences between the subcutaneous bortezomib group and the intravenous bortezomib group in the overall responses rate [OR =1.06,95％ CI (0.84,1.33)] and complete response [OR =0.93,95％ CI (0.65,1.31)].In terms of safety,the incidence of peripheral neuropathy and grade ≥3 peripheral neuropathy were significantly lower in subcutaneous bortezomib group than those in intravenous bortezomib group with siginificance [OR =0.44,95％ CI (0.35,0.56);OR =0.30,95％ CI (0.19,0.46),respectively] (P ＜ 0.001).Conclusion Subcutaneous bortezomib is as effective as intravenous bortezomib in multiple myeloma and reduce the incidence of peripheral neuropathy.

Autophagy plays an important role in plasma cell ontogeny and in the pathophysiology of multiple myeloma. Autophagy is usually considered a pro-survival mechanism, and cooperates with the ubiquitin proteasome system in maintaining the homeostasis of myeloma cells by degrading excessive and misfolded proteins for energy recycling. Therefore, the inhibition of autophagy could effectively induce death in myeloma cells, and could synergize with proteasome inhibitors. However, the excessive activation of autophagy could also lead to the extreme degradation of the organelles that induce autophagic cell death. Hence, the activation of autophagic cell death might also represent a promising approach for treating myeloma. Recent studies have demonstrated that autophagy also mediates drug resistance in myeloma cells and the complications of myeloma, while the inhibition of autophagy may reverse the response to drugs. In this study, we have mainly reviewed recent research on autophagy in relationship to the therapeutic effect, the reversal of drug resistance, and the mediation of complications.