Correction: Real-Time Analysis of Imatinib- and Dasatinib-Induced Effects on Chronic Myelogenous Leukemia Cell Interaction with Fibronectin.

Posted by rob on October 1, 2014 under Uncategorized | Comments are off for this article

Related Articles

Correction: Real-Time Analysis of Imatinib- and Dasatinib-Induced Effects on Chronic Myelogenous Leukemia Cell Interaction with Fibronectin.

PLoS One. 2014;9(9):e110070

Authors: The PLOS ONE Staff

Abstract

[This corrects the article DOI: 10.1371/journal.pone.0107367.].

PMID: 25268893 [PubMed - as supplied by publisher]

More

Maintaining low BCR-ABL signaling output to restrict CML progression and enable persistence.

Posted by rob on under Uncategorized | Comments are off for this article

Related Articles

Maintaining low BCR-ABL signaling output to restrict CML progression and enable persistence.

Curr Hematol Malig Rep. 2014 Mar;9(1):9-16

Authors: Burchert A

Abstract

Deregulated BCR-ABL oncogenic activity leads to transformation, oncogene addiction and drives disease progression in chronic myeloid leukemia (CML). Inhibition of BCR-ABL using Abl-specific kinase inhibitors (TKI) such as imatinib induces remarkable clinical responses. However, approximately only less than 15 % of all chronic-phase CML patients will remain relapse-free after discontinuation of imatinib in deep molecular remission. It is not well understood why persisting CML cells survive under TKI therapy without developing clonal evolution and frank TKI resistance. BCR-ABL expression level may be critically involved. Whereas higher BCR-ABL expression has been described as a pre-requisite for malignant CML stem cell transformation and CML progression to blast crisis, recent evidence suggests that during persistence TKI select for CML precursors with low BCR-ABL expression. Genetic, translational and clinical evidence is discussed to suggest that TKI-induced maintenance of low BCR-ABL signaling output may be potently tumor suppressive, because it abrogates oncogenic addiction.

PMID: 24500518 [PubMed - indexed for MEDLINE]

More

Haplotype analysis of the C677T and A1298C polymorphisms of MTHFR and susceptibility to chronic myeloid leukemia.

Posted by rob on under Uncategorized | Comments are off for this article

Related Articles

Haplotype analysis of the C677T and A1298C polymorphisms of MTHFR and susceptibility to chronic myeloid leukemia.

Med Oncol. 2014 Mar;31(3):871

Authors: Saadat M

PMID: 24496563 [PubMed - indexed for MEDLINE]

More

Reduced ABCG2 and increased SLC22A1 mRNA expression are associated with imatinib response in chronic myeloid leukemia.

Posted by rob on under Uncategorized | Comments are off for this article

Related Articles

Reduced ABCG2 and increased SLC22A1 mRNA expression are associated with imatinib response in chronic myeloid leukemia.

Med Oncol. 2014 Mar;31(3):851

Authors: de Lima LT, Vivona D, Bueno CT, Hirata RD, Hirata MH, Luchessi AD, de Castro FA, de Lourdes F Chauffaille M, Zanichelli MA, Chiattone CS, Hungria VT, Guerra-Shinohara EM

Abstract

Imatinib mesylate (IM) has become a standard of care in chronic myeloid leukemia (CML) therapy. Single nucleotide polymorphisms (SNPs) and altered expression in drug transporter genes may influence IM response. In order to investigate whether mRNA expression and SNPs in drug transporters are associated with IM resistance, we studied 118 chronic-phase CML patients receiving the standard dose of IM (400 mg/day). They were assigned as responders and non-responders according to European LeukemiaNet criteria (2009). mRNA expression in samples at diagnosis (without IM therapy) and outcomes after IM failure were also evaluated in subgroups of patients. Major molecular response (MMR), complete molecular response and primary and secondary resistance were all assessed. BCR-ABL1, ABCB1, ABCG2, SLC22A1 and SLCO1A2 mRNA expression and SNPs in ABCG2 and SLC22A1 genes were analyzed. ABCG2 mRNA expression in the non-responders was higher before and during IM therapy. Furthermore, ABCG2 was overexpressed in those who did not achieve MMR (P=0.027). In a subgroup of patients who switched to second-generation tyrosine kinase inhibitors, high mRNA expression of ABCG2 was associated with a risk of 24 times that of not achieving complete cytogenetic response (OR 24.00, 95% CI 1.74-330.80; P=0.018). In the responder group, patients who achieved MMR (P=0.009) presented higher mRNA levels of SLC22A1. The SNPs were not associated with mRNA expression of ABCG2 and SLC22A1. Our data suggest that elevated ABCG2 expression (an efflux transporter) could be associated with IM resistance and could impact on second-generation TKI response, whereas high SLC22A1 expression (an influx transporter) may be associated with a successful IM therapy in CML patients.

PMID: 24469953 [PubMed - indexed for MEDLINE]

More

Genetic events other than BCR-ABL1.

Posted by rob on under Uncategorized | Comments are off for this article

Related Articles

Genetic events other than BCR-ABL1.

Curr Hematol Malig Rep. 2014 Mar;9(1):24-32

Authors: Neviani P

Abstract

The BCR-ABL1 oncoprotein is the cause of chronic myeloid leukemia and occurs as a consequence of the translocation t(9;22), a well-defined genetic event that results in the formation of the Philadelphia chromosome. While this genomic aberration is recognized to be the main culprit of the chronic phase of chronic myeloid leukemia, the natural clonal evolution of this myeloproliferative neoplasm involves the accumulation of secondary alterations through genomic instability. Thus, efforts to dissect the frequency and nature of the genomic events at diagnosis and at later stages are producing valuable insights into understanding the mechanisms of blastic transformation and development of resistance in chronic myeloid leukemia. The identification of alternative BCR-ABL1-dependent and BCR-ABL1-independent targets that sustain the survival of leukemic blasts and/or leukemia-initiating cells will facilitate the development of novel viable therapeutic options for patients who become resistant or intolerant to the currently available therapeutic options based on tyrosine kinase inhibitors.

PMID: 24407376 [PubMed - indexed for MEDLINE]

More

Molecular monitoring.

Posted by rob on under Uncategorized | Comments are off for this article

Related Articles

Molecular monitoring.

Curr Hematol Malig Rep. 2014 Mar;9(1):1-8

Authors: Soverini S, Rosti G, Baccarani M, Martinelli G

Abstract

More and more potent therapeutic approaches demand more and more sophisticated response monitoring. Soon after the introduction of the first tyrosine-kinase inhibitor (TKI) for chronic myeloid leukemia (CML) treatment, real time quantitative polymerase chain reaction (RQ-PCR) became the gold standard to follow the kinetics of reduction of disease burden and allow prognostic stratification. Continuous therapeutic improvement has led to increasingly ambitious treatment endpoints (now culminating in the possibility of achieving treatment free remission), which, in turn, has led to more and more refined measurement and definition of molecular response (MR) levels. Here, we will review the evolution of molecular response definitions and terminology, how specific MR levels currently provide key checkpoints in the context of optimal patient management, how molecular monitoring can best be performed nowadays and what future trends for further technological improvement can be.

PMID: 24395452 [PubMed - indexed for MEDLINE]

More

Immunology and immunotherapy of chronic myeloid leukemia.

Posted by rob on under Uncategorized | Comments are off for this article

Related Articles

Immunology and immunotherapy of chronic myeloid leukemia.

Curr Hematol Malig Rep. 2014 Mar;9(1):17-23

Authors: Ilander M, Hekim C, Mustjoki S

Abstract

Chronic myeloid leukemia (CML) is a clonal bone marrow stem cell neoplasia known to be responsive to immunotherapy. Despite the success of tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL1 oncokinase, patients are not considered to be cured with the current therapy modalities. However, there have been recent advancements in understanding the immunobiology of the disease (such as tumor specific antigens and immunostimulatory agents), and this may lead to the development of novel, curative treatment strategies. Already there are promising results showing that a small proportion of CML patients are able to discontinue the therapy although they have a minimal amount of residual leukemia cells left. This implies that the immune system is able to restrain the tumor cell expansion. In this review, we aim to give a brief update of the novel aspects of the immune system in CML patients and of the developing strategies for controlling CML by the means of immunotherapy.

PMID: 24390549 [PubMed - indexed for MEDLINE]

More

Simultaneous manifestation of pleural effusion and acute renal failure associated with dasatinib: a case report.

Posted by rob on under Uncategorized | Comments are off for this article

Related Articles

Simultaneous manifestation of pleural effusion and acute renal failure associated with dasatinib: a case report.

J Clin Pharm Ther. 2014 Feb;39(1):102-5

Authors: Kaiafa G, Kakaletsis N, Savopoulos C, Perifanis V, Giannouli A, Papadopoulos N, Zisekas S, Hatzitolios AI

Abstract

WHAT IS KNOWN AND OBJECTIVE: Dasatinib is a novel second-generation inhibitor of multiple tyrosine kinases, indicated for the treatment for Philadelphia chromosome-positive (Ph+) chronic myeloid leukaemia (CML), acute lymphoblastic leukaemia (ALL) and lymphoid blast CML with resistance or intolerance to prior therapy. Although dasatinib is a potent, efficacious and generally well-tolerated drug, patients are also subject to various adverse effects. The most common pulmonary-related side effect is pleural effusion (PE). Renal failure has been reported rarely as a side effect of dasatinib treatment. We report the first case of a patient with imatinib-resistant CML who developed PE and acute renal failure (ARF) simultaneously, after being placed on dasatinib therapy.

CASE SUMMARY: We report a 58-year-old female dasatinib-treated patient with Ph+ chronic phase CML who was admitted to our hospital due to persisted dyspnoea and fever. After reviewing the laboratory and clinical findings, we determined our patient as having simultaneously ARF and PE related to dasatinib therapy. Dasatinib was discontinued, and after 10 days of treatment with ampicillin-sulbactam, allopurinol, amlodipine, furosemide and methylprednisolone, she was discharged home effusion free and with ameliorated renal function.

WHAT IS NEW AND CONCLUSION: PE is the most common extra-haematological toxicity observed during dasatinib treatment whose pathogenesis is still unclear. A possible role of cytokines, such as platelet-derived growth factor receptor (PDGFR)-? and vascular endothelial growth factor (VEGF), in causing endothelial permeability has been suggested. The aetiology of renal failure is also unclear in these patients, but two different possible mechanisms have been suggested such as tumour lysis syndrome and toxic tubular damage. In conclusion, here we describe the first case of simultaneous manifestation of PE and ARF associated with dasatinib. Thus, in patients treated with tyrosine kinase inhibitors, especially those with predisposing nephrological or haematological factors, serum creatinine levels should be monitored routinely.

PMID: 24188312 [PubMed - indexed for MEDLINE]

More

Wogonin Reverses Multi-Drug Resistance of Human myelogenous leukemia K562/A02 cells via Downregulation of MRP1 Expression by Inhibiting Nrf2/ARE Signaling Pathway.

Posted by rob on September 30, 2014 under Uncategorized | Comments are off for this article

Wogonin Reverses Multi-Drug Resistance of Human myelogenous leukemia K562/A02 cells via Downregulation of MRP1 Expression by Inhibiting Nrf2/ARE Signaling Pathway.

Biochem Pharmacol. 2014 Sep 25;

Authors: Xu X, Zhang Y, Li W, Miao H, Zhang H, Zhou Y, Li Z, You Q, Guo Q, Zhao L

Abstract

Constitutive NF-E2-related factor 2(Nrf2) activation has been recently reported to play a pivotal role in enhancing cell survival and resistance to anticancer drugs in many tumors. Previously, much effort has been devoted to the investigation of blocking Nrf2 function in cultured cells and cancer tissues, but few research has been undertaken to evaluate the precise mechanism of flavonoids-induced sensitivity by inhibiting Nrf2. In this study, we investaged the reversal effect of Wogonin, a flavonoid isolated from the root of Scutellaria baicalensis Georgi, in resistant human myelogenous leukemia. Data indicated that Wogonin had strong reversal potency by inhibiting functional activity and expression of MRP1 at both protein and mRNA in adriamycin(ADR)-induced resistant human myelogenous leukemia K562/A02 cells. Consequently, the inhibition of MRP1 by Wogonin was dependent on Nrf2 through the decreased binding ability of Nrf2 to antioxidant response element(ARE). Further research revealed Wogonin modulated Nrf2 through the reduction of Nrf2mRNA at transcriptional processes rather than RNA degradation, which is regulated by the PI3K/Akt pathway. Moreover, DNA-PKcs was found to be involved in the Wogonin-induced downregulation of Nrf2 mRNA at transcriptional levels. In summary, these results clearly demonstrated the effectiveness of using Wogonin via inhibiting Nrf2 to combat chemoresistance and suggested that Wogonin can be developed into an efficient natural sensitizer for resistant human myelogenous leukemia.

PMID: 25264278 [PubMed - as supplied by publisher]

More

Unexpected bone marrow finding in a patient with pancytopenia after hematopoietic stem cell transplantation.

Posted by rob on under Uncategorized | Comments are off for this article

Related Articles

Unexpected bone marrow finding in a patient with pancytopenia after hematopoietic stem cell transplantation.

Blood. 2014 Jul 31;124(5):678

Authors: Drexler B, Holbro A

PMID: 25221805 [PubMed - indexed for MEDLINE]

More

Bosutinib. Chronic myeloid leukaemia in treatment failure: major toxicity.

Posted by rob on under Uncategorized | Comments are off for this article

Related Articles

Bosutinib. Chronic myeloid leukaemia in treatment failure: major toxicity.

Prescrire Int. 2014 Jul;23(151):177

Authors:

Abstract

Retrospective analysis of data on 52 patients in whom other tyrosine kinase inhibitors had failed or were poorly tolerated. Beware of frequent and often serious adverse effects with bosutinib, including diarrhoea and hepatotoxicity.

PMID: 25162088 [PubMed - indexed for MEDLINE]

More

Deep molecular responses achieved in patients with CML-CP who are switched to nilotinib after long-term imatinib.

Posted by rob on under Uncategorized | Comments are off for this article

Related Articles

Deep molecular responses achieved in patients with CML-CP who are switched to nilotinib after long-term imatinib.

Blood. 2014 Jul 31;124(5):729-36

Authors: Hughes TP, Lipton JH, Spector N, Cervantes F, Pasquini R, Clementino NC, Dorlhiac Llacer PE, Schwarer AP, Mahon FX, Rea D, Branford S, Purkayastha D, Collins L, Szczudlo T, Leber B

Abstract

Patients in complete cytogenetic response (CCyR) with detectable BCR-ABL1 after ?2 years on imatinib were randomized to nilotinib (400 mg twice daily, n = 104) or continued imatinib (n = 103) in the Evaluating Nilotinib Efficacy and Safety in clinical Trials-Complete Molecular Response (ENESTcmr) trial. By 1 and 2 years, confirmed undetectable BCR-ABL1 was achieved by 12.5% vs 5.8% (P = .108) and 22.1% vs 8.7% of patients in the nilotinib and imatinib arms, respectively (P = .0087). Among patients without molecular response 4.5 (BCR-ABL1(IS) ?0.0032%; MR(4.5)) and those without major molecular response at study start, MR(4.5) by 2 years was achieved by 42.9% vs 20.8% and 29.2% vs 3.6% of patients in the nilotinib and imatinib arms, respectively. No patient in the nilotinib arm lost CCyR, vs 3 in the imatinib arm. Adverse events were more common in the nilotinib arm, as expected with the introduction of a new drug vs remaining on a well-tolerated drug. The safety profile of nilotinib was consistent with other reported studies. In summary, switching to nilotinib enabled more patients with chronic myeloid leukemia in chronic phase (CML-CP) to sustain lower levels of disease burden vs remaining on imatinib. This trial was registered at www.clinicaltrials.gov as #NCT00760877.

PMID: 24948656 [PubMed - indexed for MEDLINE]

More

Chronic myelomonocytic leukemia: myelodysplastic or myeloproliferative?

Posted by rob on under Uncategorized | Comments are off for this article

Related Articles

Chronic myelomonocytic leukemia: myelodysplastic or myeloproliferative?

Best Pract Res Clin Haematol. 2013 Dec;26(4):387-400

Authors: Itzkson R, Fenaux P, Solary E

Abstract

Chronic myelomonocytic leukemia (CMML) is a clonal disease of the hematopoietic stem cell that provokes a stable increase in peripheral blood monocyte count. The World Health Organisation classification appropriately underlines that the disease combines dysplastic and proliferative features. The percentage of blast cells in the blood and bone marrow distinguishes CMML-1 from CMML-2. The disease is usually diagnosed after the age of 50, with a strong male predominance. Inconstant and non-specific cytogenetic aberrations have a negative prognostic impact. Recurrent gene mutations affect mainly the TET2, SRSF2, and ASXL1 genes. Median survival is 3 years, with patients dying from progression to AML (20-30%) or from cytopenias. ASXL1 is the only gene whose mutation predicts outcome and can be included within a prognostic score. Allogeneic stem cell transplantation is possibly curative but rarely feasible. Hydroxyurea, which is the conventional cytoreductive agent, is used in myeloproliferative forms, and demethylating agents could be efficient in the most aggressive forms of the disease.

PMID: 24507815 [PubMed - indexed for MEDLINE]

More

[Adherence and toxicity to tyrosine kinase inhibitor therapy in chronic myeloid leukemia].

Posted by rob on under Uncategorized | Comments are off for this article

Related Articles

[Adherence and toxicity to tyrosine kinase inhibitor therapy in chronic myeloid leukemia].

Farm Hosp. 2013 Nov-Dec;37(6):434-40

Authors: González Rosa V, Gutiérrez Nicolás F, Gavira Moreno R, Viña Romero MM, Moreno Carvajal MT, Gázquez Pérez R

Abstract

OBJECTIVE: To analyze adherence and toxicity of tyrosine kinase inhibitor (TKIs) therapy in patients diagnosed with chronic myeloid leukemia (CML).

METHOD: A 18-months retrospective observational study (January 2011-June 2012) which included all patients diagnosed with CML in a secondary hospital (550 beds) and were treated with imatinib, dasatinib or nilotinib. It was collected the following variables: sex, age at diagnosis, years of treatment and side effects. Adherence was evaluated using SMAQ questionnaire and recording dispensations.

RESULTS: 25 patients were included and all but two (92.0%) experienced side effects to imatinib,83.3% to dasatinib and 66.7% to nilotinib. The average adherence was 71.3%. There was identified as possible parameters of lack of adherence the female patients (55.6 % vs. 66.7%, p = 0.586), older than 50 (55.6 % vs. 83.3 %, p = 0.125), more than four years of treatment (70.0 % vs. 57.1 %, p = 0.521) and the presence of certain side effects (gastrointestinal disorders and musculoeskeletal pain).

CONCLUSIONS: Almost one third of patients were considered nonadherent to therapy. Although the sample size did not allow us to establish a statistically significant relation between adherence and the variables analyzed, the clinical relevance of these results show the importance of future studies with larger populations to confirm the trends established in this study.

PMID: 24256006 [PubMed - indexed for MEDLINE]

More

Pseudoporphyria induced by imatinib mesylate.

Posted by rob on under Uncategorized | Comments are off for this article

Related Articles

Pseudoporphyria induced by imatinib mesylate.

Int J Dermatol. 2014 Feb;53(2):e143-4

Authors: Pérez NO, Esturo SV, Viladomiu Edel A, Moreno AJ, Valls AT

PMID: 23451912 [PubMed - indexed for MEDLINE]

More

Association of -174G/C interleukin/6 gene polymorphism with the risk of chronic lymphocytic, chronic myelogenous and acute myelogenous leukemias in Turkish patients.

Posted by rob on September 28, 2014 under Uncategorized | Comments are off for this article

Association of -174G/C interleukin/6 gene polymorphism with the risk of chronic lymphocytic, chronic myelogenous and acute myelogenous leukemias in Turkish patients.

J BUON. 2014 Jul-Sept;19(3):787-791

Authors: Mutlu P, Yalcin S, Elci P, Yildirim M, Cetin AT, Avcu F

Abstract

Purpose: The purpose of this study was to evaluate the relationship between -174G/C interleukin-6 (IL-6) gene promoter polymorphism and susceptibility to chronic lymphocytic (CLL), chronic myelogenous (CML) and acute myelogenous leukemia (AML) in Turkish patients. Methods: The frequencies of -174G/C polymorphism were studied in 23 unrelated CLL, 25 CML and 17 AML patients and 30 healthy individuals. Single nucleotide polymorphisms (SNPs) were genotyped by the PCR-RFLP method. Results: A higher prevalence of the C allele was found in CLL, CML and AML patients. However, there were no statistically significant differences regarding either the genotype or the allelic frequencies of the -174G/C polymorphism between CLL, CML and AML cases. Conclusions: These results indicate that C allele is associated with risk of CLL, CML and AML susceptibility in Turkish patients.

PMID: 25261668 [PubMed - as supplied by publisher]

More

Haploidentical vs cord blood transplantation for adults with acute myelogenous leukemia.

Posted by rob on September 27, 2014 under Uncategorized | Comments are off for this article

Related Articles

Haploidentical vs cord blood transplantation for adults with acute myelogenous leukemia.

World J Stem Cells. 2014 Sep 26;6(4):371-9

Authors: Solh M

Abstract

Hematopoeitic cell transplantation is established as a curative treatment for patients w acute myelogenous leukemia. Haploidentical family donor and umbilical cord blood (UCB) are alternative sources of stem cells for patients lacking a matched sibling or unrelated donor. The early challenges of transplant complications related to poor engraftment and graft-vs-host disease have been overcome with new strategies such as using 2 units and increased cell dose in UCB and T-cell depletion and post transplantation cyclophosphamide in haploidentical transplantation. The outcomes of alternative transplantation for acute leukemia were compared to other traditional graft sources. For patients lacking a matched sibling or unrelated donor, either strategy is a suitable option. The choice should rely mostly on the urgency of the transplantation and the available cell dose as well as the expertise available at the transplant center. This manuscript reviews the options of alternative donor transplantation and highlights recent advances in each of these promising transplantation options.

PMID: 25258659 [PubMed]

More

The Src homology-2 protein Shb modulates focal adhesion kinase signaling in a BCR-ABL myeloproliferative disorder causing accelerated progression of disease.

Posted by rob on under Uncategorized | Comments are off for this article

Related Articles

The Src homology-2 protein Shb modulates focal adhesion kinase signaling in a BCR-ABL myeloproliferative disorder causing accelerated progression of disease.

J Hematol Oncol. 2014;7(1):45

Authors: Gustafsson K, Jamalpour M, Trinh C, Kharas MG, Welsh M

Abstract

BACKGROUND: The Src homology-2 domain protein B (Shb) is an adapter protein operating downstream of several tyrosine kinase receptors and consequently Shb regulates various cellular responses. Absence of Shb was recently shown to reduce hematopoietic stem cell proliferation through activation of focal adhesion kinase (FAK) and thus we sought to investigate Shb’s role in the progression of leukemia.

METHODS: Wild type and Shb knockout bone marrow cells were transformed with a retroviral BCR-ABL construct and subsequently transplanted to wild type or Shb knockout recipients. Disease latency, bone marrow and peripheral blood cell characteristics, cytokine expression, signaling characteristics and colony formation were determined by flow cytometry, qPCR, western blotting and methylcellulose colony forming assays.

RESULTS: It was observed that Shb knockout BCR-ABL-transformed bone marrow cells produced a disease with death occurring at earlier time points compared with corresponding wild type controls due to elevated proliferation of transformed bone marrow cells. Moreover, significantly elevated interleukin-6 and granulocyte colony-stimulation factor mRNA levels were observed in Shb knockout c-Kit?+?leukemic bone marrow cells providing a plausible explanation for the concurrent peripheral blood neutrophilia. Shb knockout leukemic bone marrow cells also showed increased ability to form colonies in methylcellulose devoid of cytokines that was dependent on the concomitantly observed increased activity of FAK. Transplanting BCR-ABL-transformed Shb knockout bone marrow cells to Shb knockout recipients revealed decreased disease latency without neutrophilia, thus implicating the importance of niche-derived cues for the increase of blood granulocytes.

CONCLUSIONS: Absence of Shb accelerates disease progression by exerting dual roles in BCR-ABL-induced leukemia: increased cell expansion due to elevated FAK activity and neutrophilia in peripheral blood, the latter dependent on the genetic background of the leukemic niche.

PMID: 24952416 [PubMed - indexed for MEDLINE]

More

?-Arrestin1 promotes the progression of chronic myeloid leukaemia by regulating BCR/ABL H4 acetylation.

Posted by rob on under Uncategorized | Comments are off for this article

Related Articles

?-Arrestin1 promotes the progression of chronic myeloid leukaemia by regulating BCR/ABL H4 acetylation.

Br J Cancer. 2014 Jul 29;111(3):568-76

Authors: Qin R, Li K, Qi X, Zhou X, Wang L, Zhang P, Zou L

Abstract

BACKGROUND: ?-Arrestins are scaffold proteins that interact with various cellular signals. Although ?-arrestin2 mediates the initiation and progression of myeloid leukaemia, the critical role of ?-arrestin1 in the chronic myeloid leukaemia (CML) is still unknown. The aim of this study is to investigate the essential function of ?-arrestin1 in CML.

METHODS: The expressions of ?-arrestin1 and BCR/ABL in CML patients, animal models and K562 cells were measured by RT-PCR, immunofluorescence and western blotting. The effect of ?-arrestin1 on CML animal models and K562 cells by colony formation, MTT and survival analysis were assessed. BCR/ABL H4 acetylation was analysed through the use of Chromatin-immunoprecipitation (ChIP) -on-chip and confirmed by ChIP respectively. Co-immunoprecipitation and confocal were examined for the binding of ?-arrestin1 with enhancer of zeste homologue 2 (EZH2).

RESULTS: The higher expression of ?-arrestin1 is positively correlated with clinical phases of CML patients. Depletion of ?-arrestin1 decelerates progression of K562 and primary cells, and increases survival of CML mice. Importantly, silenced ?-arrestin1 results in the decrease of BCR/ABL H4 acetylation level in K562 cells. Further data illustrate that nuclear ?-arrestin1 binds to EZH2 to mediate BCR/ABL acetylation and thus regulates cell progression in K562 cells and the survival of CML mice.

CONCLUSIONS: Our findings reveal a novel function of ?-arrestin1 binding to EZH2 to promote CML progression by regulating BCR/ABL H4 acetylation.

PMID: 24937675 [PubMed - indexed for MEDLINE]

More

Polymorphisms in microRNA target sites modulate risk of lymphoblastic and myeloid leukemias and affect microRNA binding.

Posted by rob on under Uncategorized | Comments are off for this article

Related Articles

Polymorphisms in microRNA target sites modulate risk of lymphoblastic and myeloid leukemias and affect microRNA binding.

J Hematol Oncol. 2014;7(1):43

Authors: Dzikiewicz-Krawczyk A, Macieja A, Ma?y E, Januszkiewicz-Lewandowska D, Mosor M, Fichna M, Strauss E, Nowak J

Abstract

BACKGROUND: MicroRNA dysregulation is a common event in leukemia. Polymorphisms in microRNA-binding sites (miRSNPs) in target genes may alter the strength of microRNA interaction with target transcripts thereby affecting protein levels. In this study we aimed at identifying miRSNPs associated with leukemia risk and assessing impact of these miRSNPs on miRNA binding to target transcripts.

METHODS: We analyzed with specialized algorithms the 3′ untranslated regions of 137 leukemia-associated genes and identified 111 putative miRSNPs, of which 10 were chosen for further investigation. We genotyped patients with acute myeloid leukemia (AML, n?=?87), chronic myeloid leukemia (CML, n?=?140), childhood acute lymphoblastic leukemia (ALL, n?=?101) and healthy controls (n?=?471). Association between SNPs and leukemia risk was calculated by estimating odds ratios in the multivariate logistic regression analysis. For miRSNPs that were associated with leukemia risk we performed luciferase reporter assays to examine whether they influence miRNA binding.

RESULTS: Here we show that variant alleles of TLX1_rs2742038 and ETV6_rs1573613 were associated with increased risk of childhood ALL (OR (95% CI)?=?3.97 (1.43-11.02) and 1.9 (1.16-3.11), respectively), while PML_rs9479 was associated with decreased ALL risk (OR?=?0.55 (0.36-0.86). In adult myeloid leukemias we found significant associations between the variant allele of PML_rs9479 and decreased AML risk (OR?=?0.61 (0.38-0.97), and between variant alleles of IRF8_ rs10514611 and ARHGAP26_rs187729 and increased CML risk (OR?=?2.4 (1.12-5.15) and 1.63 (1.07-2.47), respectively). Moreover, we observed a significant trend for an increasing ALL and CML risk with the growing number of risk genotypes with OR?=?13.91 (4.38-44.11) for carriers of ?3 risk genotypes in ALL and OR?=?4.9 (1.27-18.85) for carriers of 2 risk genotypes in CML. Luciferase reporter assays revealed that the C allele of ARHGAP26_rs187729 creates an illegitimate binding site for miR-18a-3p, while the A allele of PML_rs9479 enhances binding of miR-510-5p and the C allele of ETV6_rs1573613 weakens binding of miR-34c-5p and miR-449b-5p.

CONCLUSIONS: Our study implicates that microRNA-binding site polymorphisms modulate leukemia risk by interfering with the miRNA-mediated regulation. Our findings underscore the significance of variability in 3′ untranslated regions in leukemia.

PMID: 24886876 [PubMed - indexed for MEDLINE]

More