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Imatinib resistance: a review of alternative inhibitors in chronic myeloid leukemia
Bitencourt, Roberta;Zalcberg, Ilana;Louro, Iúri Drumond;
Revista Brasileira de Hematologia e Hemoterapia , 2011, DOI: 10.5581/1516-8484.20110124
Abstract: the development of point mutations in the bcr-abl kinase domain is the main reason for imatinib resistance in chronic myeloid leukemia. different detection methods are used in chronic myeloid leukemia monitoring, such as direct sequencing, denaturing high performance liquid chromatography and allele specific polymerase chain reaction. mutation analysis has become mandatory during patient workup of chronic myeloid leukemia in order for the physician to choose the most suitable tyrosine kinase inhibitor. this article, a review of possible therapies used to overcome imatinib resistance, investigates the current position by searching the pubmed electronic database using the following keywords: imatinib, dasatinib, nilotinib, aurora kinase, src kinase, mutation, treatment, drugs and resistance. new tyrosine kinase inhibitors include bcr-abl kinase selective inhibitors, dual abl/src kinase inhibitors and aurora kinase inhibitors. awareness of the spectrum of new drugs against mutations, in particular the t315i mutation, makes it possible to properly select the best therapy for each patient.
Methylation status of the SOCS 1 and JUNB genes in chronic myeloid leukemia patients
Pena, Márcia Cristina R.;Pardini, Maria Inês M. C.;Colturato, Virgilio A. R.;Pinheiro, Nídia A.;
Revista Brasileira de Hematologia e Hemoterapia , 2009, DOI: 10.1590/S1516-84842009005000050
Abstract: alterations in the methylation status of genes may contribute to the progression of chronic myeloid leukemia (cml). in this study, the methylation status in exon2 of socs- 1 and promoter regions of both socs- 1 and junb were evaluated in cml patients. the methylation status of these genes was analyzed using methylation- specific polymerase chain reaction (msp) in 30 samples from cml patients, 30 samples from these same patients after hematopoietic stem cell transplantation (hsct) and 30 samples from healthy controls. the samples of cml patients presented methylation as follows: junb gene (3.3%), promoter region of the socs- 1 gene (6.6%) and exon2 of the socs- 1 gene (46.6%). the samples of the healthy individuals presented methylation (10%, p = 0.002) only in exon 2 of the socs- 1 gene. after transplantation, patients presented alterations in the methylation status of the promoter region of the socs- 1 gene (6.6%), exon2 of socs- 1 (46.6%) and the promoter region of the junb gene (16.6%). methylation of the promoter regions of the socs- 1 gene and the junb gene is not a frequent event in cml. in contrast, socs- 1 gene methylation in exon2 is a frequent event, susceptible to alterations in status after hsct with possible implications for the progression of this disease.
Investigation of P16INK4A and P14RF Genes Expression in Different Phase of Chronic Myeloid Leukemia (CML)
SH Mousavi,Y Mortazavi,H Dargahi,N Shayan
Payavard Salamat , 2008,
Abstract: Background & Aim : Chronic myeloid leukemia (CML) is a disorder of pluripotential hematopoietic stem cell that is as a myeloproliferative disease and occurs in about 15 percent of all leukemia. Two cell cycle regulatory proteins that function as tumor suppressor are P16INK4A and P14ARF. The origin of these two proteins is a human INK4A-ARF gene locus that located on chromosome 9p21. P16INK4A control retinoblastoma (Rb) and P14ARF control with p53 thought negative feedback. The purposes of this study, this was that whether these genes are preferable use as a factor in prognosis and progression of disease.Materials and Methods: This research was a Cross sectional study. The expression of p16INK4A and p14ARF mRNA in about 73 peripheral bloods (PB) Samples were collected from 45 CML patients at different phases of disease were assayed by reverse transcriptase polymerase chain reaction (RT-PCR). 26 samples were from patients at chronic phase before any treatment, 26 samples 3 month after treatment with imatinib, 9 samples in accelerated phase and 12 samples in Blastic phase.Results. From 45 patients with CML, 33 patients (73%) were men and 12 patients (27%) were women. About 26 samples (35%) were p16INK4A positive and 55 samples (75%) were p14ARF RT-PCR positive. This expression of the two genes at different phases of disease were not statistically significant (p>0.05).Conclusion: High percentage of the CML patients expressed P14ARF and P16INK4A genes. The expression of these gene at different phases of disease (diagnosis, accelerate, and Blastic phases) was not statistically significant; even though, the expression of these genes was higher after the treatment. The increased expression of these genes was probably because of the Imatinib treatment.
The role of natural killer cells in chronic myeloid leukemia
Danier, Anna Carolyna Araújo;Melo, Ricardo Pereira de;Napimoga, Marcelo Henrique;Laguna-Abreu, Maria Theresa Cerávolo;
Revista Brasileira de Hematologia e Hemoterapia , 2011, DOI: 10.5581/1516-8484.20110057
Abstract: chronic myeloid leukemia is a neoplasia resulting from a translocation between chromosomes 9 and 22 producing the bcr-abl hybrid known as the philadelphia chromosome (ph). in chronic myeloid leukemia a proliferation of malignant myeloid cells occurs in the bone marrow due to excessive tyrosine kinase activity. in order to maintain homeostasis, natural killer cells, by means of receptors, identify the major histocompatibility complex on the surface of tumor cells and subsequently induce apoptosis. the nkg2d receptor in the natural killer cells recognizes the transmembrane proteins related to major histocompatibility complex class i chain-related genes a and b (mica and micb), and it is by the interaction between nkg2d and mica that natural killer cells exert cytotoxic activity against chronic myeloid leukemia tumor cells. however, in the case of chronic exposure of the nkg2d receptor, the mica ligand releases soluble proteins called smica from the tumor cell surface, which negatively modulate nkg2d and enable the tumor cells to avoid lysis mediated by the natural killer cells. blocking the formation of smica may be an important antitumor strategy. treatment using tyrosine kinase inhibitors induces modulation of nkg2dl expression, which could favor the activity of the natural killer cells. however this mechanism has not been fully described in chronic myeloid leukemia. in the present study, we analyze the role of natural killer cells to reduce proliferation and in the cellular death of tumor cells in chronic myeloid leukemia.
Monitoring imatinib plasma concentrations in chronic myeloid leukemia
Martins, Darlize Hübner;Wagner, Sandrine Comparsi;Santos, Tamyris Vianna dos;Lizot, Lilian de Lima Feltraco;Antunes, Marina Venzon;Capra, Marcelo;Linden, Rafael;
Revista Brasileira de Hematologia e Hemoterapia , 2011, DOI: 10.5581/1516-8484.20110081
Abstract: imatinib has proved to be effective in the treatment of chronic myeloid leukemia, but plasma levels above 1,000 ng/ml must be achieved to optimize activity. therapeutic drug monitoring of imatinib is useful for patients that do not present clinical response. there are several analytical methods to measure imatinib in biosamples, which are mainly based on liquid chromatography with mass spectrometric or diode array spectrophotometric detection. the former is preferred due to its lower cost and wider availability. the present manuscript presents a review of the clinical and analytical aspects of the therapeutic drug monitoring of imatinib in the treatment of chronic myeloid leukemia. the review includes references published over the last 10 years. there is evidence that the monitoring of plasmatic levels of imatinib is an useful alternative, especially considering the wide pharmacokinetic variability of this drug.
Diagnosis of Chronic Myeloid Leukemia Early in Pregnancy  [PDF]
Fabio Stagno, Paolo Vigneri, Massimo Poidomani, Stefania Stella, Alessandra Cupri, Michele Massimino, Livia Manzella, Francesco Di Raimondo
Open Journal of Blood Diseases (OJBD) , 2011, DOI: 10.4236/ojbd.2011.11001
Abstract: Imatinib therapy has revolutionized the clinical course of Chronic Myeloid Leukemia. The unexpected prolonged survival raised several issues on the quality of life and on the possibility to parent childs.
Chronic myeloid leukemia: past, present, future  [PDF]
Patricia Weinschenker Bollmann,Auro del Giglio
Einstein (S?o Paulo) , 2011,
Abstract: The discovery of the Philadelphia chromosome in 1960, and of theBCR-ABL oncogene in 1984, enabled the development in subsequentyears of a targeted therapy that revolutionized the treatment of chronic myeloid leukemia, thus changing its natural history. The use of imatinib resulted in a significant improvement of the prognosis and outcome of patients with chronic myeloid leukemia. However, the occurrence of mechanisms of resistance or intolerance precludes the eradication of the disease in some of the patients. Second-generation tyrosinekinase inhibitors are efficient in most of these patients, except for those with T315I mutation. We present an overall review of chronic myeloid leukemia, with emphasis on the progress in its treatment.
Frequency of BCR-ABL Fusion Transcript in Iranian Patients with Chronic Myeloid Leukemia
Yaghmaie M.,Ghaffari S.H.,Alimoghaddam K.,Ghavamzadeh A.
International Journal of Hematology-Oncology and Stem Cell Research , 2005,
Abstract: Introduction: Reverse transcriptase-polymerase chain reaction (RT-PCR) assay is a useful tool for the detection of fusion transcript resulting from specific chromosomal translocation of the leukemia cells. A specific chromosomal abnormality, the Philadelphia chromosome (Ph), is present in 90% to 95% of CML patients.The aberration results from a reciprocal translocation between chromosome 9 and 22, creating a BCR-ABL fusion gene.There are two major forms of the BCR/ABL fusion gene, involving ABL exon 2, but including different exons of BCR gene. The transcripts b2a2 or b3a2 code for a p210 protein. Another fusion gene leads to the expression of an e1a2 transcript, which codes for a p190 pro-tein. Another, less common fusion genes are b3a3 or b2a3 (p203) and e19a2 (p230). The incidence of one or other rearrangement in chronic myeloid leukemia (CML) patients varies in different reported se-ries. In general, fusion transcripts are determined individually, a process which is labor intensive in or-der to detect all major fusion transcripts. Methods: This study was designed to determine the frequency of different fusion genes in 75 iranian patients with CML. peripheral blood samples were analyzed by multiplex reverse transcriptase poly-merase chain reaction (RT-PCR) from adult patients to detect all types of BCR-ABL transcripts of the t (9:22) and found that all cases were positive for some type of BCR/ABL rearrangement. Results: Most of our patients showed b3a2 fusion gene (62%), while the remaining showed one of the transcripts of b2a2, b3a3, b2a3, e1a2 or coexpression of b3a2 and b2a2. The rate of coexpression of the b3a2 and b2a2 was 5%. Conclusion: In contrast to the other reports, we did not see any coexpression of p210/p190. This may reflect either the sensitivity of the detection techniques used or the possibility of genetic differences be-tween the populations studied. Coexpression may be due to alternative splicing or to phenotypic varia-tion, with clinical course different from classical CML.
Advances in the treatment of chronic myeloid leukemia
Anna M Eiring, Jamshid S Khorashad, Kimberly Morley, Michael W Deininger
BMC Medicine , 2011, DOI: 10.1186/1741-7015-9-99
Abstract: Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm caused by BCR-ABL, a chimeric gene generated as a result of a reciprocal translocation [t(9;22)(q34;q11), cytogenetically visible as the Philadelphia chromosome (Ph)] that places sequences from the ABL gene from chromosome 9 downstream of the BCR gene on chromosome 22. The fact that tyrosine kinase activity of BCR-ABL is conditio sine qua non for the protein's ability to transform cells led to the development of small molecule tyrosine kinase inhibitors (TKIs) [1]. It is a little more than ten years ago that the first TKI, imatinib, was approved for the treatment of chronic myeloid leukemia (CML) patients who had failed prior therapy with interferon-α (IFN). Two years later, the International Randomized Study of Interferon and STI571 (IRIS) study demonstrated the superiority of imatinib over IFN/cytarabine (the standard drug therapy at the time), in newly diagnosed chronic phase patients, and led to its approval for first-line therapy [2]. Prior to the development of imatinib, effective treatment for CML was limited to a minority of patients. IFN-based regimens prolonged survival compared to hydroxyurea, with induced durable responses in 10-30% of patients [3,4]. However, this benefit was largely limited to patients with low risk according to Sokal and came at the expense of significant toxicity. Allogeneic hematopoietic stem cell transplant in first chronic phase from a matched related donor produced five-year disease-free survival rates of approximately 50%. However, transplant-related mortality and morbidity were considerable and many patients were not eligible due to co-morbidities or lack of a suitable donor [5]. All this changed radically with the advent of imatinib. We now have the luxury of asking questions that would have seemed presumptuous just ten years ago, foremost whether we can safely discontinue imatinib in patients whose disease is consistently undetectable by RT-PCR. The logical exten
Detection of mutator phenotype in Brazilian patients with acute and chronic myeloid leukemia
Ayres, Flávio Monteiro;Momotuk, Euza Guimar?es;Bastos, Celso da Cunha;Cruz, Aparecido Divino da;
Genetics and Molecular Biology , 2004, DOI: 10.1590/S1415-47572004000400003
Abstract: the multisteps of tumorigenesis involve the classic chromosomal instability and the mutator phenotype pathways featured by a predisposition to acquire mutations in tumor suppressor genes and oncogenes. expansion and contraction of microsatellite sequences due to a deficient mismatch repair system are a marker of the mutator phenotype. controversial results regarding the extent of microsatellite instability (msi) have been reported in the development and progression of myeloid malignancies. here, we investigated msi and loss of heterozygosity (loh) frequencies at the microsatellite loci bat-26, d7s486, d8s135, ank1, ifna, tp53 and bcr of 19 brazilian patients with acute (aml) and chronic myeloid leukemia (cml). one aml patient and one cml patient were categorized as having a high degree of microsatellite instability (msi-h), corresponding to 10.5% (2/19) of all patients. loh at loci bat-26 and tp53 was present in 30% of the patients with aml alone. despite the small sample size, our results suggest that the mutator phenotype, as verified by msi frequency, could play a role in the leukemogenesis of a small subset of patients with myeloid leukemia.
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