Yuling Li

CDKN2 Gene Deletion as Poor Prognosis Predictor Involved in the Progression of Adult B-Lineage Acute Lymphoblastic Leukemia Patients

Deletion of cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) is well known in many hematologic malignancies, but only few reports have investigated this deletion effect on clinical prognosis. This study performed analysis of the CDKN2 deletion in 215 adult B- lineage acute lymphoblastic leukemia (B-ALL) patients, and related cytogenetic prognostic factors (BCR/ABL; E2A/PBXl; TEL/AML1; Mixed Lineage Leukemia (MLL) rearrangement; MYC, Immunoglobulin heavy locus (IGH) translocation). The prevalence of CDKN2 deletions in all study populations was 28.4%. There is no difference between patients with CDKN2 deletion and wild-type patients in sex, age, white blood cells (WBC) count, BM blast percentage, extra infiltration and induction complete remission (CR) rate. Analysis in relapse patients revealed that the distribution of CDKN2 deletion is higher in relapse patients (44.6%) than all patients (28.4%, P=0.006). Deletion of CDKN2 was significantly associated with poor outcomes including decreased overall survival (OS) (P<0.001), lower disease free-survival (DFS) (P<0.001), and increased cumulative incidence of relapse (P=0.002); Also, CDKN2 deletion was strongly associated with IGH translocation (P=0.021); and had an adverse effect on patients with BCR-ABL fusion gene or with MLL rearrangement. Patients with CDKN2 gene deletion benefited from allogenic hematopoietic stem cell transplantation (Allo-HSCT). Deletion of CDKN2 gene was commonly observed through leukemia progression and was poor prognostic marker in long-term outcomes.

A comparative proteomic study of Homoharringtonine-induced apoptosis in leukemia K562 cells

Abstract The objective of this study was to determine the changes in protein profiles of K562 chronic myeloid leukemia (CML) cells in response to Homoharringtonine (HHT). HHT treatment significantly increased apoptosis of K562 cells. Proteomic analyses indicated 32 differentially expressed proteins, 13 of which were identified by mass spectrometry (nine down-regulated and four up-regulated). Aside from alterations in apoptotic proteins and proteins associated with transcription and translation, our data also revealed changes in oxidative stress response and redox reaction-related proteins, such as heat shock proteins (Hsps), DJ-1 and thioredoxin. Specifically, these proteins were validated to decrease after HHT treatment in K562 cells and in primary CML cells by immunoblot analysis. Additionally, Hsps, DJ-1 and thioredoxin, which were also shown to decrease in primary cells from imatinib-resistant patients, may be promising potential targets for mechanistic research and new clinical treatments.

Correlation between deletion of the CDKN2 gene and tyrosine kinase inhibitor resistance in adult Philadelphia chromosome-positive acute lymphoblastic leukemia

BackgroundFrequency relapses are common in Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukemia (ALL) following tyrosine kinase inhibitors (TKIs). CDKN2A/B is believed to contribute to this chemotherapy resistance.MethodsTo further investigate the association between CDKN2 status and TKI resistance, the prevalence of CDKN2 deletions and its correlation with a variety of clinical features was assessed in 135 Ph-positive ALL patients using interphase fluorescence in situ hybridization (I-FISH).ResultsResults showed that no difference occurred between patients with CDKN2 deletion (44/135) and wild-type patients in sex, age, and complete remission (CR) rate following induction chemotherapy combined with tyrosine kinase inhibitors (TKIs). However, CDKN2 deletion carriers demonstrated higher white blood cell (WBC) count, enhanced rates of hepatosplenomegaly (P = 0.006), and upregulation of CD20 expression (P = 0.001). Moreover, deletions of CDKN2 resulted in lower rates of complete molecular response (undetectable BCR/ABL), increased cumulative incidence of relapse, short overall survival (OS), and disease-free survival (DFS) time (P < 0.05) even though these patients received chemotherapy plus TKIs followed by allogenic hematopoietic stem cell transplantation (Allo-HSCT). In the case of 44 patients who presented with CDKN2 deletion, 18 patients were treated with dasatinib treatment, and another 26 patients were treated with imatinib therapy, and our study found that there were no differences associated with OS (P = 0.508) and DFS (P = 0.555) between the two groups.ConclusionsCDKN2 deletion is frequently acquired during Ph-positive ALL progression and serves as a poor prognostic marker of long-term outcome in Ph-positive ALL patients with CDKN2 deletion even after the second-generation tyrosine kinase inhibitor treatment.

Prognostic Significance of Monosomal Karyotype in Adult Patients With Acute Myeloid Leukemia Treated With Risk-Adapted Protocols

BACKGROUND The monosomal karyotype (MK) is a well-known adverse prognostic factor and has been found to be related to poor outcome in patients with acute myeloid leukemia (AML). However, the outcome in MK-positive AML patients undergoing different therapies has not been well investigated. PATIENTS AND METHODS We retrospectively analyzed clinical and laboratory features in 225 MK-positive AML patients. Clinical outcome of overall survival (OS) and disease-free survival (DFS) was evaluated in patients according to age group and in patients who received different therapy protocols. RESULTS The proportion of MK-positive patients increased along with age. Also, patients who were treated with high-dose cytarabine (HD-Ara-C) as consolidation therapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) demonstrated longer OS and DFS compared to allo-HSCT or HD-Ara-C alone. Patients treated with allo-HSCT alone exhibited longer DFS compared to patients treated with HD-Ara-C alone. No difference in OS was discovered between these 2 single protocols. CONCLUSION MK was associated with a lower complete remission rate. HD-Ara-C therapy followed by allo-HSCT could improve the prognosis of MK-positive AML patients.

Therapeutic immune monitoring of CD4+CD25+ T cells in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors

Tyrosine kinase inhibitors (TKIs), including imatinib, dasatinib and nilotinib, are effective forms of therapy for various types of solid cancers and Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia. A number of TKIs have been known to have strong effects on T cells, particularly cluster of differentiation (CD) 4+CD25+ T cells, also known as regulatory T cells (Tregs). There is currently a deficit in the available clinical data regarding this area of study. In the present study, a total of 108 peripheral blood samples were collected from patients with chronic myeloid leukemia (CML) at diagnosis (n=31), and at 3 and 6 months following treatment with TKI [imatinib (n=12), dasatinib (n=11) and nilotinib groups (n=8)] and healthy controls (n=15). Peripheral blood mononuclear cells were collected from the patients prior to and following TKI treatment. The subtype and number of T lymphocytes in patients and healthy donors were analyzed using flow cytometry. Additionally, flow cytometry and ELISA were used to detect the proliferation and suppression of Tregs. Expression of cytokines and other molecules [forkhead box P3 (FOXP3), glucocorticoid-induced tumor necrosis factor receptor (GITR) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)] were also analyzed at 3 and 6 months following treatment with TKIs. It was indicated that, at diagnosis, a similar number of lymphocytes were detected in patients and control. However, following treatment with a TKI, the number of total T cells, Tregs, CD4+ T and CD8+ T cells decreased to various degrees in patients. Furthermore, the decrease in the number of Tregs was more significant with time. Although treatment with imatinib, dasatinib and nilotinib demonstrated similar inhibitory effects on the quantity of Tregs in vivo, the TKIs exhibited differential effects on the function of Tregs in vitro. Proliferation, suppression and expression of cytokines [interleukin (IL)-4, IL-10 and transforming growth factor (TGF)-β] and molecules (FOXP3, GITR and CTLA-4) decreased significantly in treatment groups with imatinib and dasatinib. The decrease was not significant in the nilotinib treatment group. Imatinib and dasatinib may exert more marked inhibitory roles compared with nilotinib on regulating the number and function of Tregs. These results suggest that personalized treatment and follow-up of CML patients during TKI treatment, particularly for those who received post-transplant TKI treatment may be beneficial.

EphB4/ephrinB2 Contributes to Imatinib Resistance in Chronic Myeloid Leukemia Involved in Cytoskeletal Proteins

Introduction: The mechanism of EphB4/ephrinB2 in the resistance of chronic myelogenous leukemia to imatinib keeps unknown. Methods: The imatinib resistant chronic myelogenous leukemia cell line-K562-R, was established. EphB4 receptor expression was detected in patients and resistant cells. Cell migration and drug sensitivity were tested in the EphB4 knockdown cells and mouse models. Results: The EphB4 receptor was over-expressed in blast crisis patients compared to chronic phase patients. The level of EphB4 receptor expression was associated with a complete cytogenetic response within 12 months. Enhanced expression of the EphB4 receptor was detected in the K562-R cells. EphB4 knockdown inhibited cell migration ability and restored sensitivity to imatinib in vitro and in vivo. Restored sensitivity to imatinib was observed in K562-R cells, along with increased levels of phospho-EphB4 and decreased phosphorylation levels of RhoA, Rac1, and Cdc42. Conclusion: Our study illustrates that aberrant activation of EphB4/ephrinB2 may mediate chronic myeloid leukemia resistance involved in cytoskeletal proteins.