Toward therapeutic effects evaluation of chronic myeloid leukemia drug: electrochemical platform for caspase-3 activity sensing.
Biosens Bioelectron. 2014 Nov 15;61:648-54
Authors: Zhou S, Zheng T, Chen Y, Zhang J, Li L, Lu F, Zhu JJ
In recent decades, advanced therapies and novel scientific drug evaluation systems for chronic myeloid leukemia (CML) treatment are very urgent due to its increasing morbidity. The combination of dasatinib with tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) was supposed to be effective for leukemia therapy. Taking full advantage of novel nano-biotechnology, we have developed a robust electrochemical cytosensing approach to profile the therapeutic effects of dasatinib and TRAIL by probing the activity of caspase-3 from apoptotic CML cells. The sensor was on a base of a glassy carbon electrode (GCE) modified with nano-materials composed of Au nanoparticles (AuNPs), poly(dimethyl diallyl ammonium chloride) (PDDA), and carbon nanotubes (CNTs). Then the platform immobilized the biotinylated DEVD-peptide (biotin-Gly-Asp-Gly-Asp-Glu-Val-Asp-Gly-Cys) via the strong bonding between AuNPs and the thiol group (Au-S bond). In particular, the sensor was then constructed with the environmentally friendly alkaline phosphatase (ALP) via the specific interaction between the biotin and streptavidin, and could retest detection indirectly for caspase-3 sensing by detecting the differential pulse voltammetry (DPV) signal of enzymatic catalysis product, ascorbic acid (AA). The results indicated that either dasatinib or TRAIL could successfully induce the apoptosis of CML cells, while the combination of dasatinib and TRAIL resulted in an improved therapeutic effect, suggesting a novel optimized strategy for CML therapy. This novel electrochemical sensing strategy exhibits attractive advantages of environmental benignity, simple performance, high stability, and may be readily expanded to evaluate other cancer therapeutic effects.
PMID: 24976045 [PubMed - indexed for MEDLINE]
MTHFR A1298C and C677T gene polymorphisms and susceptibility to chronic myeloid leukemia in Egypt.
Int J Clin Exp Pathol. 2014;7(5):2571-8
Authors: Aly RM, Taalab MM, Ghazy HF
Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating the intracellular folate metabolism which plays an important role in carcinogenesis through DNA methylation. We aimed to evaluate the association between MTHFR A1298C and C677T polymorphisms and the risks of chronic myeloid leukemia (CML). Eighty-five patients with CML and a control group containing 100 healthy, age and sex matched individuals were examined for MTHFR C677T and A1298C polymorphisms using polymerase chain reaction-restriction fragment-length (PCR-RFLP) method. The frequency of 677TT genotype in patients with CML was significantly higher compared to controls (OR=2.513, 95% CI: 0.722-4.086, P=0.025). No such association was shown for heterozygous 677CT (OR=1.010, 95% CI: 0.460-2.218, P=0.981). Moreover, for A1298C genotype, a statistically significant higher frequency of 1298CC was also detected in CML patients compared to control group (OR=1.1816, 95% CI: 0.952-3.573, P=0.036), 0.036). No such statistical significance was demonstrable for heterozygote 1298AC (OR=1.046, 95% CI: 0.740-1.759, P=0.092). In addition, patients with joint 677CT/1298AC or 677TT/1298CC genotypes showed an association with increased risk of CML (OR=1.849, 95% CI: 0.935-2.540, P=0.024; OR=1.915, 95% CI: 1.202-3.845, P=0.020 respectively). .A statistically significant increased risk of resistant to therapy was observed with 677CT and 1298AC genotypes (P=0.001, P=0.002 respectively). We conclude that both MTHFR 677TT and 1298CC polymorphisms have been associated with risk of CML and both 677CT and 1298AC genotypes are associated with higher risk of resistant to therapy.
PMID: 24966971 [PubMed - indexed for MEDLINE]
Analysis of BCR/ABL transcripts in healthy individuals.
Genet Mol Res. 2013;12(4):4967-71
Authors: Boquett JA, Alves JR, de Oliveira CE
The chimeric oncogene BCR/ABL, which is the product of reciprocal translocation between chromosomes 9 and 22, is a known molecular marker of chronic myeloid leukemia (CML), and is related to the major factors involved in leukemogenesis. Some previous studies have also reported the presence of this oncogene in peripheral blood cells of healthy individuals. In this study, we investigated the presence of BCR/ABL transcripts in peripheral blood of individuals aged 40 years or more without symptoms of CML. The presence of BCR/ABL transcripts was observed in 2 of the 30 individuals analyzed. The genesis of BCR/ABL transcripts and its presence in healthy individuals are topics of ongoing debate. The risks and biological implications of the presence of BCR/ABL transcripts in healthy individuals are challenging issues that remain to be elucidated.
PMID: 24301757 [PubMed - indexed for MEDLINE]
Maximizing GVL in allogeneic transplantation: role of donor lymphocyte infusions.
Hematology Am Soc Hematol Educ Program. 2014 Dec 5;2014(1):570-575
Authors: Nikiforow S, Alyea EP
Donor lymphocyte infusions (DLIs) can induce complete and durable remissions in some patients with hematologic malignancies who have relapsed after allogeneic transplantation, providing definitive evidence of a GVL effect. Despite the great promise initially envisioned for DLI as a method to augment GVL after transplantation, it utility is limited by low response rates in diseases other than chronic myelogenous leukemia and by the development of GVHD, the principal complication of DLI. To maximize GVL potency while minimizing toxicity, cellular effectors active in GVL need to be elucidated. Insight into mechanisms of GVL, such as reversal of in situ T-cell exhaustion, may allow identification of patients who will respond to DLI based on the presence of tumor-infiltrating lymphocytes in the BM. Understanding the clinical factors that influence the effectiveness and abrogate the toxicity of DLI, such as cell dose and timing of DLI after transplantation, will allow further optimization of DLI. This chapter reviews novel strategies that maximize the GVL effect of DLI by enhancing activity while limiting toxicity.
PMID: 25696913 [PubMed - as supplied by publisher]
Pediatric secondary chronic myeloid leukemia following cardiac transplantation for anthracycline-induced cardiomyopathy.
Pediatr Blood Cancer. 2015 Jan;62(1):166-8
Authors: Menon NM, Katsanis E, Khalpey Z, Whitlow P
Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of the hematopoietic stem cell that is exceptionally rare in the first five years of life, particularly as a secondary malignancy. This report describes a case of secondary CML in a four-year-old female occurring after AML treatment. Interestingly, CML developed while on immunosuppression for a heart transplant due to anthracycline-induced cardiomyopathy.
PMID: 25175922 [PubMed - indexed for MEDLINE]
[Allogeneic hematopoietic stem cell transplantation for aggressive-phase chronic myeloid leukemia -- outcomes of unrelated umbilical cord blood and sibling donor].
Zhonghua Xue Ye Xue Za Zhi. 2014 Mar;35(3):253-5
Authors: Lu Y, Sun Z, Liu H, Geng L, Tong J, Tang B, Zheng C, Yao W, Song K
PMID: 24666498 [PubMed - indexed for MEDLINE]
[A clinical and laboratory study of chronic myeloid leukemia with atypical BCR-ABL fusion gene subtypes].
Zhonghua Xue Ye Xue Za Zhi. 2014 Mar;35(3):210-4
Authors: Gui X, Pan J, Qiu H, Cen J, Xue Y, Chen S, Shen H, Yao L, Zhang J, Wu Y, Chen Y
OBJECTIVE: To explore the clinical and laboratory features of chronic myeloid leukemia (CML) with atypical e14a3 and e19a2 BCR-ABL fusion gene subtypes.
METHODS: We retrospectively analyzed a cohort of CML patients with Ph chromosome positive confirmed by cytogenetic and FISH but classical e13a3(b2a2), e14a2(b3a2)and e1a2 fusion transcripts negative identified by conventional real-time quantification RT-PCR (RQ-PCR). Further RQ-PCR was done with the forward primer and reverse primer designed to detect rare atypical BCR-ABL fusion genes including e14a3 and e19a2 transcripts. Direct sequencing analysis was performed on the PCR products and mutations in the BCR-ABL kinase domain were detected. The clinical data of patients were retrospectively analyzed.
RESULTS: Six CML patients were found to carry t(9;22) abnormality and BCR-ABL rearrangement confirmed by FISH but classical BCR-ABL fusion genes negative detected by RQ-PCR. Further RQ-PCR and sequencing analysis confirmed the fusion of BCR exon 14 and ABL exon 3 in five CML patients (case 1-5) and the fusion of BCR exon 19 and ABL exon 2 in one CML patient (case 6). E255K and I293T IM-resistant mutations were detected in case 1 and 2, respectively. Among five cases with e14a3 transcripts, four were CML-CP, one CML-AP. Four patients were male and one was female. The median age was 48 years. The patient (case 6) with e19a2 transcripts was 40-year-old female with a diagnosis of CML-CP and PLT count was more than 1 000×10?/L. Imatinib (IM) therapy was administer in case 1, 2, 3, 4 and hematopoietic stem cell transplantation (HSCT) was undergone in case 5 after hydroxyurea (Hu) or interferon failure. Case 1 who had E255K IM resistant mutation, responded poorly to IM but obtained a complete cytogenetic remission (CCyR) after a substitution of dasatinib for IM. Case 2 and 3 achieved CCyR 6 months later after IM treatment and had been maintained well with IM despite I293T mutation in case 2. Case 4 attained CCyR 3 months later after IM treatment but relapsed and died soon. Case 5 was still in CCyR after HSCT. Case 6 with e19a2 transcripts got complete hematologic response after Hu treatment and CCyR was achieved soon after IM therapy.
CONCLUSION: Incidence of CML with atypical transcripts is extremely low. They could benefit from tyrosine kinase inhibitors or HSCT. Rare and atypical BCR- ABL fusion gene subtypes could be missed by conventional RQ-PCR.
PMID: 24666486 [PubMed - indexed for MEDLINE]
[Hotsport report of the 55th American Society of Hematology Annual Meeting: chronic myeloid leukemia].
Zhonghua Xue Ye Xue Za Zhi. 2014 Feb;35(2):183-4
Authors: He X, Wu D
PMID: 24606668 [PubMed - indexed for MEDLINE]
[Deep molecular response: the new target of treatment of chronic myeloid leukemia?].
Zhonghua Xue Ye Xue Za Zhi. 2014 Feb;35(2):176-9
Authors: Jiang Q
PMID: 24606666 [PubMed - indexed for MEDLINE]
[Pilot treatment for 13 BCR-ABL positive leukemia patients with T315I mutation].
Zhonghua Xue Ye Xue Za Zhi. 2014 Feb;35(2):162-4
Authors: Zhou M, Sha X, Qiu H, Cen J, Shen H, Sun A, Wu D
PMID: 24606661 [PubMed - indexed for MEDLINE]
[Detection of leukemia-derived microparticles in the monitoring of chronic myeloid leukemia].
Zhonghua Xue Ye Xue Za Zhi. 2014 Feb;35(2):138-41
Authors: Zhu X, Li Q, Zeng C, Zhong Z, You Y, Zou P
OBJECTIVE: To exam the role of leukemia cells-derived microparticles in the post-complete molecular response stratification.
METHODS: Blood samples from 29 patients diagnosed with chronic myeloid leukemia (CML) were collected. Microparticles (MP) were extracted from the peripheral blood. Real-time PCR was performed to measure the level of BCR-ABL mRNA.
RESULTS: BCR-ABL mRNA could be stably detected both in MP and peripheral blood cells; BCR-ABL in MP showed significant difference within complete molecular response, major molecular response and complete cytogenetic response (9.1±2.8, 25.2±6.9 and 62.8±6.3 respectively, P<0.05). BCR-ABL was detected in MP even when it was negative in peripheral blood cells (3.7-15.3). For patients with complete molecular response, BCR-ABL in MP but not cells were significantly different between imatinib and stem cell transplant recipients (3.3±2.1 vs 9.1±2.8, P<0.05).
CONCLUSION: This study indicated that MP may serves as a new target for monitoring of CML. Quantification of BCR-ABL in MP may offer a novel strategy for stratification of molecular response.
PMID: 24606656 [PubMed - indexed for MEDLINE]
[A multicenter study on the validation of conversion factor for the conversion of BCR-ABL (P210) transcript levels to the international scale in chronic myeloid leukemia].
Zhonghua Xue Ye Xue Za Zhi. 2014 Feb;35(2):134-7
Authors: Qin Y, Lin Z, Cen J, Li X, Li Q, Cheng H, Geng S, Wang Y, Ma D, Qiao C, Li J, Li L, Huang X
OBJECTIVE: To validate the conversion factor (CF) for the conversion of BCR-ABL (P210) transcript levels to the international scale in chronic myeloid leukemia (CML).
METHODS: In 2012, the international reference laboratory in Adelaide, Australia (IMVS) sent two batches of RNA samples, 30 samples per batch, to Peking University People’s Hospital (PKUPH). By comparing BCRABL (P210) transcript levels reported by the two laboratories, CF of PKUPH was calculated and validated by IMVS. In 2013, PKUPH prepared the exchange samples for validation of CF of 9 hospitals who have calculated CFs before. The fresh BCR-ABL (P210) (+) cells were serially diluted by BCR-ABL (P210) (-) cells to prepare 22 kinds of samples with different BCR-ABL transcript levels, each kind had 10 parallel samples. Trizol reagent was added in each tube. Ten hospitals tested BCR-ABL transcript levels of one set of 22 samples. Agreement between BCR-ABL transcript levels of each laboratory and PKUPH was assessed by the Bland-Altman method.
RESULTS: PKUPH successfully validated its CF with bias 1.1 fold and 95% limits of agreement between -4.7 and 4.9 fold. Of 9 hospitals whose validation performed by sample exchanges with PKUPH, 6 hospitals successfully validated their CF with bias ?±1.4 fold and 95% limits of agreement within ±6 fold.
CONCLUSION: Validation of CF examined the stability of the detection of BCR-ABL (P210) transcript levels, which was necessary for the valid conversion of BCR-ABL (P210) transcript levels to the international scale in CML.
PMID: 24606655 [PubMed - indexed for MEDLINE]
[Second-generation tyrosine kinase inhibitors combined with allogeneic hematopoietic stem cell transplant for Philadelphia chromosome positive leukemia].
Zhonghua Xue Ye Xue Za Zhi. 2014 Feb;35(2):129-33
Authors: Yu X, Li C, Wu X, Ye L, Liu H, Ma C, Ma J, Gu C, Wu D
OBJECTIVE: To investigate the efficacy and safety of second-generation tyrosine kinase inhibitors (TK-II) combined with allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the treatment of high-risk Philadelphia chromosome positive (Ph?) leukemia.
METHODS: The clinical data of 17 cases of high-risk Ph? leukemia patients underwent allo-HSCT were retrospectively analyzed, including 1 case in accelerated phase and 7 cases in blast crises of chronic myeloid leukemia, and 9 cases of Ph? acute lymphoblastic leukemia. Nilotinib or Dasatinib were administered before and (or) after allo-HSCT in all patients.
RESULTS: All patients successfully engrafted. Median times to neutrophil and platelet recovery were 12 days (range 10-14) and 15 days (range 11- 23), respectively. Acute GVHD developed in 7 patients: 6 patients had grade 1 to 2 and 1 patient grade 3. Chronic GVHD developed in 6 patients, all were limited and no lethal GVHD occurred. At a median follow-up of 17(range 3-60) months, 11(64.7%) patients survived disease free, 6 patients relapsed and 5 died.
CONCLUSION: TK-II combined with allo-HSCT effectively improved the remission rate of high-risk Ph? leukemia and reduced recurrence after allo-HSCT, which represented an important improvement in the treatment of patients with high-risk Ph+ leukemia.
PMID: 24606654 [PubMed - indexed for MEDLINE]
[Outcomes of imatinib and allogeneic hematopoietic stem cell transplantation in the treatment of chronic myeloid leukemia].
Zhonghua Xue Ye Xue Za Zhi. 2014 Feb;35(2):126-8
Authors: Zhou M, Sha X, Qiu H, He G, Xu Y, Cen J, Pan J, Chen S, Sun A, Zhang R, Wu D
OBJECTIVE: To compare the curative effect of imatinib and allogeneic hematopoietic stem cell transplant (allo-HSCT) in the treatment of chronic myeloid leukemia (CML).
METHODS: 292 CML patients received imatinib, and 141 patients underwent allo-HSCT. The clinical data of these patients were retrospectively analyzed to compare event- free survival (EFS) and overall survival (OS) between these two groups of patients in chronic and advanced (including accelerate and blast) phases.
RESULTS: (1) EFS, OS, expected 5- year EFS and OS of imatinib group (278 patients in chronic phase) were all statistically higher than of allo-HSCT group (120 patients in chronic phase) (88.5% vs 70.0%, 93.2% vs 80.0%, 84.0% vs 75.0% and 92.0% vs 79.0%, respectively, all P values < 0.01). (2) EFS and OS of imatinib group (14 patients in accelerate and blast phases) were 42.9% and 42.9%, respectively. Meanwhile EFS and OS of allo-HSCT group (21 patients in accelerate and blast phases) were 47.6% and 57.1%, respectively. There were no significant differences in terms of EFS and OS between the two groups (P values>0.05).
CONCLUSION: EFS and OS of imatinib group were significantly higher than of allo-HSCT group for CML patients of in chronic phase. Imatinib and allo-HSCT had the similar efficacy for CML patients in accelerate and blast phases.
PMID: 24606653 [PubMed - indexed for MEDLINE]
[Comparison of simultaneous bone marrow cytogenetic and peripheral blood molecular responses in chronic myeloid leukemia].
Zhonghua Xue Ye Xue Za Zhi. 2014 Feb;35(2):104-8
Authors: Lai Y, Qin Y, Huang X, Jiang Q
OBJECTIVE: Compare the correlation and the concordance of simultaneous bone marrow cytogenetic and peripheral blood molecular responses in patients with chronic myeloid leukemia (CML) during tyrosine kinase inhibitor (TKI) treatment.
METHODS: A total of 1 030 pairs of simultaneous bone marrow and peripheral blood samples from 419 patients with CML during TKI treatment were analyzed with standard G-banding techniques and real-time quantitative reverse transcriptase PCR (Q-PCR).
RESULTS: The Spearman correlation coefficient for the paired analysis of the percentage of Ph- positive metaphases versus Q-PCR (BCR-ABL/ABL) values was 0.655 (n=1 030, P<0.01). There was a significant difference in terms of BCR-ABL values among all three cytogenetic response groups of no partial cytogenetic (no PCyR), partial cytogenetic (PCyR) and complete cytogenetic responses(CCyR) (P<0.01). 93.8% of the patients in CCyR had BCR-ABL?1% [International Scale (IS)], and 97.5% of those with BCR-ABL?0.1% (IS) were in CCyR. There was good concordance of 86.2% (888 of 1 030 samples) when BCR-ABL values according to cutoffs of BCR-ABL>10%(IS), ?10%->1%(IS)and ?1%(IS) were coupled with cytogenetic responses including no PCyR, PCyR and CCyR. Furthermore, 497 pairs of samples from 279 patients with newly diagnosed CML in chronic phase during the first year on TKI as first-line therapy were analyzed. Concordances between major cytogenetic response and BCR-ABL?10%(IS) at 3 months, CCyR and BCR-ABL?1%(IS) at 6 months and 12 months were 89%, 83.5% and 92.1%, respectively.
CONCLUSION: There were significant correlation and concordance between cytogenetic and molecular responses, and some differences in assessment of early responses between using cytogenetic and molecular analyses in CML patients during TKI treatment.
PMID: 24606648 [PubMed - indexed for MEDLINE]
[The significance of international standardization on molecular monitoring in chronic myeloid leukemia].
Zhonghua Xue Ye Xue Za Zhi. 2014 Feb;35(2):102-3
Authors: Qin Y
PMID: 24606647 [PubMed - indexed for MEDLINE]
[Cytogenetic and molecular monitoring in the treatment of chronic myeloid leukemia].
Zhonghua Xue Ye Xue Za Zhi. 2014 Feb;35(2):101-2
Authors: Du X
PMID: 24606646 [PubMed - indexed for MEDLINE]
[Can the second-generation tyrosine kinase inhibitors be as first-line treatment strategy in newly diagnosed chronic phase chronic myeloid leukemia patients?].
Zhonghua Xue Ye Xue Za Zhi. 2014 Feb;35(2):99-100
Authors: Zou P
PMID: 24606645 [PubMed - indexed for MEDLINE]
[Clinical significance of analysis of BCR- ABL kinase domain mutation in chronic myeloid leukemia patients].
Zhonghua Xue Ye Xue Za Zhi. 2014 Feb;35(2):95-7
Authors: Jin J, Yin X
PMID: 24606643 [PubMed - indexed for MEDLINE]
[The effect of tyrosine kinase inhibitor on outcome of allogeneic hematopoietic stem cell transplant for the treatment of chronic myeloid leukaemia].
Zhonghua Xue Ye Xue Za Zhi. 2014 Feb;35(2):94-5
Authors: Xu L, Ma Y
PMID: 24606642 [PubMed - indexed for MEDLINE]