BCR-ABL1-associated reduction of beta catenin antagonist Chibby1 in chronic myeloid leukemia.

Posted by rob on March 3, 2015 under Uncategorized | Comments are off for this article

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BCR-ABL1-associated reduction of beta catenin antagonist Chibby1 in chronic myeloid leukemia.

PLoS One. 2013;8(12):e81425

Authors: Leo E, Mancini M, Aluigi M, Luatti S, Castagnetti F, Testoni N, Soverini S, Santucci MA, Martinelli G

Abstract

Beta Catenin signaling is critical for the self-renewal of leukemic stem cells in chronic myeloid leukemia. It is driven by multiple events, enhancing beta catenin stability and promoting its transcriptional co-activating function. We investigated the impact of BCR-ABL1 on Chibby1, a beta catenin antagonist involved in cell differentiation and transformation. Relative proximity of the Chibby1 encoding gene (C22orf2) on chromosome 22q12 to the BCR breakpoint (22q11) lets assume its involvement in beta catenin activation in chronic myeloid leukemia as a consequence of deletions of distal BCR sequences encompassing one C22orf2 allele. Forty patients with chronic myeloid leukemia in chronic phase were analyzed for C22orf2 relocation and Chibby1 expression. Fluorescent in situ hybridization analyses established that the entire C22orf2 follows BCR regardless of chromosomes involved in the translocation. In differentiated hematopoietic progenitors (bone marrow mononuclear cell fractions) of 30/40 patients, the expression of Chibby1 protein was reduced below 50% of the reference value (peripheral blood mononuclear cell fractions of healthy persons). In such cell context, Chibby1 protein reduction is not dependent on C22orf2 transcriptional downmodulation; however, it is strictly dependent upon BCR-ABL1 expression because it was not observed at the moment of major molecular response under tyrosine kinase inhibitor therapy. Moreover, it was not correlated with the disease prognosis or response to therapy. Most importantly, a remarkable Chibby1 reduction was apparent in a putative BCR-ABL1+ leukemic stem cell compartment identified by a CD34+ phenotype compared to more differentiated hematopoietic progenitors. In CD34+ cells, Chibby1 reduction arises from transcriptional events and is driven by C22orf2 promoter hypermethylation. These results advance low Chibby1 expression associated with BCR-ABL1 as a component of beta catenin signaling in leukemic stem cells.

PMID: 24339928 [PubMed - indexed for MEDLINE]

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Conditional Transformation Models for Survivor Function Estimation.

Posted by rob on February 27, 2015 under Uncategorized | Comments are off for this article

Conditional Transformation Models for Survivor Function Estimation.

Int J Biostat. 2015 Feb 10;

Authors: Möst L, Hothorn T

Abstract

Abstract In survival analysis, the estimation of patient-specific survivor functions that are conditional on a set of patient characteristics is of special interest. In general, knowledge of the conditional survival probabilities of a patient at all relevant time points allows better assessment of the patient’s risk than summary statistics, such as median survival time. Nevertheless, standard methods for analysing survival data seldom estimate the survivor function directly. Therefore, we propose the application of conditional transformation models (CTMs) for the estimation of the conditional distribution function of survival times given a set of patient characteristics. We used the inverse probability of censoring weighting approach to account for right-censored observations. Our proposed modelling approach allows the prediction of patient-specific survivor functions. In addition, CTMs constitute a flexible model class that is able to deal with proportional as well as non-proportional hazards. The well-known Cox model is included in the class of CTMs as a special case. We investigated the performance of CTMs in survival data analysis in a simulation that included proportional and non-proportional hazard settings and different scenarios of explanatory variables. Furthermore, we re-analysed the survival times of patients suffering from chronic myelogenous leukaemia and studied the impact of the proportional hazards assumption on previously published results.

PMID: 25719339 [PubMed - as supplied by publisher]

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"Preleukemic or smoldering" chronic myelogenous leukemia (CML):BCR-ABL1 positive: A brief case report.

Posted by rob on February 25, 2015 under Uncategorized | Comments are off for this article

“Preleukemic or smoldering” chronic myelogenous leukemia (CML):BCR-ABL1 positive: A brief case report.

Leuk Res Rep. 2015;4(1):12-4

Authors: Bennett JM, Dsouza KG, Patel M, O’Dwyer K

Abstract

Chronic myelogenous leukemia (CML), in the Chronic Phase (CP), is often suspected as a result of a complete blood count (CBC), which shows increased granulocytes, mostly mature including a peak in myelocytes, increased basophils, and rarely blasts and/or promyelocytes. Morphologic dysplasia is not present. CML is confirmed by detecting the characteristic Philadelphia chromosome (Ph)[t(9;22)(q34;q11.2)] by routine cytogenetics or fluorescent in situ hybridization (FISH) or molecular studies (RT-PCR) for the bcr-abl fusion gene. The most common feature of CML is an elevated WBC count, usually above 25×10(3)/µL, and frequently above 100×10(3)/µL. We report a case of confirmed Ph+CML with a normal CBC detected because of the presence of rare myelocytes and 2% basophils [Fig. 1]. Previous leukocyte counts for the preceding eight years were normal with the exception of one done four months prior to his presentation that showed an abnormal differential with 1% basophils, 2% metamyelocytes and 2% myelocytes.

PMID: 25709891 [PubMed]

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Transient presence of clonal chromosomal aberrations in Ph-negative cells in patients with chronic myeloid leukemia remaining in deep molecular response on tyrosine kinase inhibitor treatment.

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Transient presence of clonal chromosomal aberrations in Ph-negative cells in patients with chronic myeloid leukemia remaining in deep molecular response on tyrosine kinase inhibitor treatment.

Cancer Genet. 2014 Oct-Dec;207(10-12):503-10

Authors: Gniot M, Lewandowski K, Ratajczak B, Lewandowska M, Lehmann-Kopyd?owska A, Jarmu?-Szymczak M, Komarnicki M

Abstract

Advancements in treatment of chronic myeloid leukemia (CML) turned this formerly fatal neoplasm into a manageable chronic condition. Therapy with tyrosine kinase inhibitors (TKIs) often leads to significant reduction of disease burden, known as the deep molecular response (DMR). Herein, we decided to analyze the cohort of CML patients treated in our center with TKIs, who obtain and retain DMR for a period longer than 24 months. The aim of the study was to evaluate the frequency of clonal cytogenetic aberrations in Philadelphia-negative (Ph-) cells in patients with DMR during TKI treatment. The analyzed data was obtained during routine molecular and cytogenetic treatment monitoring, using G-banded trypsin and Giemsa stain (GTG) karyotyping and reverse transcription quantitative PCR. We noticed that approximately 50% of patients (28 of 55) in DMR had, at some follow-up point, transient changes in the karyotype of their Ph- bone marrow cells. In 9.1% of cases (5 of 55), the presence of the same aberrations was observed at different time points. The most frequently appearing aberrations were monosomies of chromosomes 19, 20, 21, and Y. Statistical analysis suggests that the occurrence of such abnormalities in CML patients correlates with the TKI treatment time.

PMID: 25496750 [PubMed - indexed for MEDLINE]

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BCR-ABL1 promotes leukemia by converting p27 into a cytoplasmic oncoprotein.

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BCR-ABL1 promotes leukemia by converting p27 into a cytoplasmic oncoprotein.

Blood. 2014 Nov 20;124(22):3260-73

Authors: Agarwal A, Mackenzie RJ, Besson A, Jeng S, Carey A, LaTocha DH, Fleischman AG, Duquesnes N, Eide CA, Vasudevan KB, Loriaux MM, Firpo E, Cortes JE, McWeeney S, O’Hare T, Roberts JM, Druker BJ, Deininger MW

Abstract

Recent studies have revealed that p27, a nuclear cyclin-dependent kinase (Cdk) inhibitor and tumor suppressor, can acquire oncogenic activities upon mislocalization to the cytoplasm. To understand how these antagonistic activities influence oncogenesis, we dissected the nuclear and cytoplasmic functions of p27 in chronic myeloid leukemia (CML), a well-characterized malignancy caused by the BCR-ABL1 tyrosine kinase. p27 is predominantly cytoplasmic in CML and nuclear in normal cells. BCR-ABL1 regulates nuclear and cytoplasmic p27 abundance by kinase-dependent and -independent mechanisms, respectively. p27 knockdown in CML cell lines with predominantly cytoplasmic p27 induces apoptosis, consistent with a leukemogenic role of cytoplasmic p27. Accordingly, a p27 mutant (p27(CK-)) devoid of Cdk inhibitory nuclear functions enhances leukemogenesis in a murine CML model compared with complete absence of p27. In contrast, p27 mutations that enhance its stability (p27(T187A)) or nuclear retention (p27(S10A)) attenuate leukemogenesis over wild-type p27, validating the tumor-suppressor function of nuclear p27 in CML. We conclude that BCR-ABL1 kinase-dependent and -independent mechanisms convert p27 from a nuclear tumor suppressor to a cytoplasmic oncogene. These findings suggest that cytoplasmic mislocalization of p27 despite BCR-ABL1 inhibition by tyrosine kinase inhibitors may contribute to drug resistance, and effective therapeutic strategies to stabilize nuclear p27 must also prevent cytoplasmic mislocalization.

PMID: 25293778 [PubMed - indexed for MEDLINE]

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Gambogic acid induces death of K562 cells through autophagy and apoptosis mechanisms.

Posted by rob on February 24, 2015 under Uncategorized | Comments are off for this article

Gambogic acid induces death of K562 cells through autophagy and apoptosis mechanisms.

Leuk Lymphoma. 2015 Feb 20;:1-22

Authors: Chen J, Zhou M, Zhang Q, Xu J, Ouyang J

Abstract

Abstract This study was aimed to detect the effects of gambogic acid (GA) on the growth of chronic myelogenous leukemia (CML) K562 cells. Our results showed that GA induced the accumulation of autophagic vacuoles and up-regulation of two autophagy-related proteins (Beclin 1 and LC3). GA also induced down-regulation of the mRNA levels of BCR/ABL fusion genes and SQSTM1/sequestosome 1 (p62) protein levels. After treatment by chloroquine (CQ) and Pan Caspase Inhibitor Z-VAD-FMK (PC), both GA induced autophagy and apoptosis were inhibited. Our study demonstrates that GA may induce cell death through autophagy and apoptosis pathways in CML K562 cells. A cross-talk mechanism exists between GA-induced autophagy and apoptosis. However, the mechanism of GA on inducing autophagy and apoptosis need further clarification.

PMID: 25699654 [PubMed - as supplied by publisher]

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A pharmacodynamic model of Bcr-Abl signalling in chronic myeloid leukaemia.

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A pharmacodynamic model of Bcr-Abl signalling in chronic myeloid leukaemia.

Cancer Chemother Pharmacol. 2014 Oct;74(4):765-76

Authors: Jackson RC, Radivoyevitch T

Abstract

Chronic myeloid leukaemia (CML) is an unusual malignancy in which myeloid progenitor cells are transformed by a single chromosomal translocation where the Bcr domain of chromosome 22 is placed adjacent to the proto-oncogene c-Abl of chromosome 9, resulting in constitutive Abl tyrosine kinase activity. This has a twofold effect: it causes increased numbers of myeloid progenitor cells and circulating myeloid cells, and it causes leakage of reactive oxygen species from mitochondria. We describe a kinetic and pharmacodynamic (PD) model of Bcr-Abl signalling in myeloid cells that is used to simulate effects of four classes of drugs: Bcr-Abl signalling inhibitors, such as imatinib, cyclin-dependent kinase inhibitors, and pro- and anti-oxidants. The model also has the potential to describe the PD effects of agents acting on other sites in the Bcr-Abl signalling pathway. Having calibrated the model against dose-response curves of these drugs acting as single agents on Bcr-Abl-transformed cells in vitro, the model was used to predict effects of the agents in combination. Used in conjunction with pharmacokinetic models, our PD model enables an approach to protocol optimization: large numbers of doses and timings and (in the case of combination treatments) relative dose ratios can be simulated in silico. Predicted selectivity, as well as efficacy, can be extracted from the model. An understanding of the Bcr-Abl signalling pathway has implications for strategies to prevent acquired drug resistance, and for preventing or delaying CML progression to its blast phase.

PMID: 25107570 [PubMed - indexed for MEDLINE]

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The current status of ponatinib in the treatment of chronic myeloid leukemia.

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The current status of ponatinib in the treatment of chronic myeloid leukemia.

Clin Adv Hematol Oncol. 2014 May;12(5):329-31

Authors: Deininger M

PMID: 25003490 [PubMed - indexed for MEDLINE]

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Toward therapeutic effects evaluation of chronic myeloid leukemia drug: electrochemical platform for caspase-3 activity sensing.

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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

Abstract

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]

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MTHFR A1298C and C677T gene polymorphisms and susceptibility to chronic myeloid leukemia in Egypt.

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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

Abstract

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]

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Analysis of BCR/ABL transcripts in healthy individuals.

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Analysis of BCR/ABL transcripts in healthy individuals.

Genet Mol Res. 2013;12(4):4967-71

Authors: Boquett JA, Alves JR, de Oliveira CE

Abstract

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]

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Maximizing GVL in allogeneic transplantation: role of donor lymphocyte infusions.

Posted by rob on February 20, 2015 under Uncategorized | Comments are off for this article

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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

Abstract

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]

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Pediatric secondary chronic myeloid leukemia following cardiac transplantation for anthracycline-induced cardiomyopathy.

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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

Abstract

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]

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[Allogeneic hematopoietic stem cell transplantation for aggressive-phase chronic myeloid leukemia -- outcomes of unrelated umbilical cord blood and sibling donor].

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[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]

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[A clinical and laboratory study of chronic myeloid leukemia with atypical BCR-ABL fusion gene subtypes].

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[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

Abstract

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]

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[Hotsport report of the 55th American Society of Hematology Annual Meeting: chronic myeloid leukemia].

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[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]

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[Deep molecular response: the new target of treatment of chronic myeloid leukemia?].

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[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]

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[Pilot treatment for 13 BCR-ABL positive leukemia patients with T315I mutation].

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[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]

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[Detection of leukemia-derived microparticles in the monitoring of chronic myeloid leukemia].

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[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

Abstract

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]

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[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].

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[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

Abstract

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]

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