scholarly journals F359C mutation of the BCR-ABL1 gene in adolescent with chronic myeloid leukemia. Case report

2019 ◽  
Vol 6 (2) ◽  
pp. 72-75
Author(s):  
M. V. Borisevich ◽  
T. V. Savitskaya
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Clinical Case ◽  
Point Mutations ◽  
Kinase Domain ◽  
Review Of The Literature ◽  
Pediatric Practice ◽  
Imatinib Resistance ◽  
Secondary Resistance ◽  
I Gene

Chronic myeloid leukemia (CML) in children is rare, less than 3 % of all cases of leukemia in pediatric practice. Along with the successes achieved in the treatment of CML with imatinib, it’s necessary to study of molecular factors in predicting resistance to therapy. According to the literature, about 30 % of adult patients with imatinib resistance have point mutations in the kinase domain of BCR-ABL1 gene. The number of reports about mutation spectrum of the BCR-ABL1 gene in children with resistant forms of CML is limited. This article describes the clinical case of secondary resistance to imatinib in a 15-year-old girl with the F359C mutation of BCR-ABL1 gene and a review of the literature.

scholarly journals BCR-ABL SH3-SH2 domain mutations in chronic myeloid leukemia patients on imatinib

Blood ◽  
2010 ◽  
Vol 116 (17) ◽  
pp. 3278-3285 ◽  
Author(s):  
Daniel W. Sherbenou ◽  
Oliver Hantschel ◽  
Ines Kaupe ◽  
Stephanie Willis ◽  
Thomas Bumm ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Point Mutations ◽  
Kinase Domain ◽  
Sh2 Domain ◽  
Common Mechanism ◽  
Regulatory Domain ◽  
Imatinib Resistance

Abstract Point mutations in the kinase domain of BCR-ABL are the most common mechanism of drug resistance in chronic myeloid leukemia (CML) patients treated with ABL kinase inhibitors, including imatinib. It has also been shown in vitro that mutations outside the kinase domain in the neighboring linker, SH2, SH3, and Cap domains can confer imatinib resistance. In the context of ABL, these domains have an autoinhibitory effect on kinase activity, and mutations in this region can activate the enzyme. To determine the frequency and relevance to resistance of regulatory domain mutations in CML patients on imatinib, we screened for such mutations in a cohort of consecutive CML patients with various levels of response. Regulatory domain mutations were detected in 7 of 98 patients, whereas kinase domain mutations were detected in 29. One mutation (T212R) conferred in vitro tyrosine kinase inhibitor resistance and was associated with relapse, whereas most other mutations did not affect drug sensitivity. Mechanistic studies showed that T212R increased the activity of ABL and BCR-ABL and that T212R-induced resistance may be partially the result of stabilization of an active kinase conformation. Regulatory domain mutations are uncommon but may explain resistance in some patients without mutations in the kinase domain.

In Early-Chronic Phase Chronic Myeloid Leukemia Patients Treated with Imatinib, Resistance Is Rarely Mediated by Abl Kinase Domain Mutations.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1934-1934 ◽  
Author(s):  
Simona Soverini ◽  
Alessandra Gnani ◽  
Sabrina Colarossi ◽  
Fausto Castagnetti ◽  
Elisabetta Abruzzese ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Point Mutations ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Kinase Domain ◽  
Line Treatment ◽  
Front Line ◽  
Imatinib Resistance

Abstract Point mutations in the kinase domain (KD) of the Bcr-Abl gene are generally regarded as the most frequent mechanism of resistance to the tyrosine kinase inhibitor (TKI) imatinib mesylate (IM) in patients (pts) with chronic myeloid leukemia (CML). Nearly all studies, however, have focused mainly on pts with advanced disease, where resistance is most often observed. Nowadays, the great majority of pts on IM are early chronic phase (ECP) pts receiving IM as front-line treatment. If, on one hand, the IRIS study demonstrated that response rates are high and relapse is infrequent in ECP, on the other hand we still know very little on the contribution of KD mutations to resistance in this subset of pts. Between January 2005 and July 2007 we analyzed for the presence of Abl KD mutations one hundred and two ECP pts on IM who were referred to our laboratory because their response was defined either as ‘failure’ (n=70 pts) or as ‘suboptimal’ (n=32 pts) according to recently published recommendations (Baccarani et al, Blood 2006). Twenty mutations were detected in 17/70 (24%) pts who failed IM. In particular, mutations were observed in 1/2 pts who showed no hematologic response (HR) at 3 months, 1/10 (10%) pts who showed less than partial cytogenetic response (PCgR) at 12 months, 4/25 (16%) pts who showed less than complete cytogenetic response (CCgR) at 18 months, 6/23 (26%) pts who lost CCgR, 5/10 (50%) pts who lost HR. Mutations were M244V (n=2), G250E (n=1), Y253H (n=4), E255K (n=1), T277A (n=1), E279K (n=1), F311I (n=1), T315I (n=1), M351T (n=3), E355D (n=1), F359V (n=1), H396R (n=3). In 7 pts who progressed to accelerated or blastic phase shortly after, four had mutations: Y253H (n=2 pts), E255K (n=1 pt) and T315I (n=1 pt). Four mutations were detected in 4/32 (13%) pts who had a suboptimal response to IM. In particular, a mutation was observed in 1/11 (9%) pts who showed less than PCgR at 6 months and in 3/21 (14%) pts who showed less than CCgR at 12 months. Mutations were E255K, F317L, M351T, F359V. In both groups no correlation was observed between likelihood of mutation selection and Sokal risk score. We conclude that in ECP pts who receive IM as front-line treatment Abl KD mutations are not the major mechanism of drug-resistance, probably because mutations tend to accumulate during the natural course of the disease as a result of a progressively increasing genetic instability and are therefore a feature of CML clinical deterioration rather than a phenomenon observed only against a background of IM exposure. Our data highlight the need to find out which is the actual predominant mechanism(s) of resistance acting in the setting of ECP - which now gathers the overwhelming majority of CML pts on IM therapy - as a mandatory step towards the development of effective second-line treatment strategies.

Nilotinib Therapy in Patients with Chronic Myeloid Leukemia Who Have Failed Imatinib

2009 ◽  
Vol 02 ◽  
pp. 30
Author(s):  
Ronan Swords ◽  
Kevin Kelly ◽  
Francis J Giles ◽  
◽  
◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Point Mutations ◽  
Standard Of Care ◽  
Kinase Domain ◽  
Current Standard ◽  
Imatinib Resistance ◽  
Prior Therapy ◽  
Advanced Phase ◽  
Failure Point

Chronic myeloid leukemia (CML) results from a single translocation that produces the BCR–ABL fusion oncogene, which is detectable in virtually all patients. Imatinib mesylate has radically changed the outlook for newly diagnosed patients and represents the current standard of care for this disorder. While most patients do well well with imatinib upfront, a minority of patients do not. In addition, this therapy offers little benefit for patients with advanced-phase disease. Several mechanisms underlie imatinib failure, point mutations within the Abelson tyrosine (ABL) kinase domain being the most significant of these. The development of novel agents designed to overcome imatinib resistance led to the creation of the high-affinity BCR-ABL inhibitor nilotinib. The purpose of this article is to summarize the pre-clinical and clinical data on nilotinib in patients with CML who have failed prior therapy with imatinib or dasatinib.

Mutation Analysis of ABL1 Gene and its Relation to the Achievement of Major Molecular Response in Indonesian Chronic Myeloid Leukemia Patients

2020 ◽  
Vol 17 (1) ◽  
pp. 48-54
Author(s):  
Reni Widyastuti ◽  
Melva Louisa ◽  
Ikhwan Rinaldi ◽  
Riki Nova ◽  
Instiaty Instiaty ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Imatinib Mesylate ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Kinase Domain ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Cross Sectional ◽  
Imatinib Resistance

Background: Imatinib mesylate is the first tyrosine kinase inhibitor approved for chronic myeloid leukemia (CML) therapy. Imatinib is an effective drug. However, previous studies have shown that about 20-30% of patients eventually would develop resistance to imatinib. Approximately 40% of imatinib resistance is associated with BCRABL kinase domain mutation. One of the most common and serious variations account for imatinib response is T315I of ABL1 gene. Objective: The study aimed to examine the association of T315I mutation with the ABL1 gene and its relation to major molecular response (MMR) achievement in CML patients. This study also examined other mutations adjacent to T315I, i.e., F311I, F317L, and different possible variations in the ABL1 gene. Methods: This was a cross-sectional study on Indonesian CML patients in chronic phase. We analyzed 120 blood samples from patients in chronic phase who have received imatinib mesylate (IM) for ≥12 months. Results: There were no T315I, F311I, and F317L mutations found in this study. However, we found another variation, which was 36 substitutions from A to G at position 163816 of ABL1 gene (according to NG_012034.1). Conclusions: We found no T315I, F311I, and F317L mutations in this study. Our findings suggest that there might be other factors that influenced the MMR achievement in our study patients. However, there were 36 substitutions from A to G at position 163.816 (according to NG_012034.1) that needed further examination to explore the significance of this mutation in clinical practice.

scholarly journals Denaturing-HPLC-Based Assay for Detection of ABL Mutations in Chronic Myeloid Leukemia Patients Resistant to Imatinib

2004 ◽  
Vol 50 (7) ◽  
pp. 1205-1213 ◽  
Author(s):  
Simona Soverini ◽  
Giovanni Martinelli ◽  
Marilina Amabile ◽  
Angela Poerio ◽  
Michele Bianchini ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Large Scale ◽  
Kinase Inhibitor ◽  
Direct Sequencing ◽  
Point Mutations ◽  
Kinase Domain ◽  
Imatinib Treatment ◽  
Abl Tyrosine Kinase ◽  
Reverse Transcription Pcr

Abstract Background: Despite the efficacy of the BCR-ABL tyrosine kinase inhibitor Imatinib mesylate for the treatment of chronic myeloid leukemia (CML), resistance has been observed in a proportion of cases, especially those with advanced stages of the disease. Point mutations within the ABL kinase domain are emerging as the most frequent mechanism for reactivation of kinase activity within the leukemic clone. Methods: We developed a denaturing-HPLC (D-HPLC)-based assay for screening for ABL point mutations. For each sample, two partially overlapping fragments of 393 and 482 bp corresponding to the kinase domain were amplified by nested reverse transcription-PCR and analyzed under selected temperature and acetonitrile gradient conditions. Fifty-one bone marrow and/or peripheral blood specimens from 27 CML patients who showed cytogenetic resistance to Imatinib were screened in parallel by D-HPLC and by direct sequencing. Results: In 12 of 27 (44%) patients, D-HPLC showed an abnormal elution profile suggesting the presence of a nucleotide change. Direct sequencing confirmed the presence of a point mutation in all cases. Conversely, all samples scored as wild type by D-HPLC showed no evidence of mutations by direct sequencing. In two cases, novel amino acid substitutions at codons already known for being hot-spots of mutation were identified (F311I and E355D). Conclusions: The proposed D-HPLC-based assay is highly specific and at least as sensitive as sequencing; with respect to the latter, it provides a much faster and less expensive semiautomated system for mutational screening. It may therefore potentially be a valuable tool for regular, large-scale testing of patients undergoing Imatinib treatment.

High frequency of point mutations clustered within the adenosine triphosphate–binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance

Blood ◽  
2002 ◽  
Vol 99 (9) ◽  
pp. 3472-3475 ◽  
Author(s):  
Susan Branford ◽  
Zbigniew Rudzki ◽  
Sonya Walsh ◽  
Andrew Grigg ◽  
Chris Arthur ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Chronic Myeloid Leukemia ◽  
Adenosine Triphosphate ◽  
High Frequency ◽  
Myeloid Leukemia ◽  
Lymphoblastic Leukemia ◽  
Point Mutations ◽  
Atp Binding ◽  
Binding Region ◽  
Imatinib Resistance

Abstract Point mutations were found in the adenosine triphosphate (ATP) binding region of BCR/ABL in 12 of 18 patients with chronic myeloid leukemia (CML) or Ph-positive acute lymphoblastic leukemia (Ph+ ALL) and imatinib resistance (defined as loss of established hematologic response), but they were found in only 1 of 10 patients with CML with imatinib refractoriness (failure to achieve cytogenetic response). In 10 of 10 patients for whom samples were available, the mutation was not detected before the initiation of imatinib therapy. Three mutations (T315I, Y253H, and F317L present in 3, 1, and 1 patients, respectively) have a predicted role in abrogating imatinib binding to BCR/ABL, whereas 3 other mutations (E255K, G250E, and M351T, present in 4, 2, and 2 patients, respectively) do not. Thus we confirm a high frequency of mutations clustered within the ATP-binding region of BCR/ABL in resistant patients. Screening may allow intervention before relapse by identifying emerging mutations with defined impacts on imatinib binding. Certain mutations may respond to higher doses of imatinib, whereas other mutations may mandate switching to another therapeutic strategy.

Characteristics of BCR–ABL kinase domain point mutations in Chinese imatinib-resistant chronic myeloid leukemia patients

2010 ◽  
Vol 90 (1) ◽  
pp. 47-52 ◽  
Author(s):  
YaZhen Qin ◽  
ShanShan Chen ◽  
Bin Jiang ◽  
Qian Jiang ◽  
Hao Jiang ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Point Mutations ◽  
Kinase Domain ◽  
Abl Kinase ◽  
Imatinib Resistant

scholarly journals ASXL1 Mutations Detectable at Diagnosis May Predict Response to Imatinib in Patients with Chronic Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4148-4148
Author(s):  
Marcin M Machnicki ◽  
Monika Pepek ◽  
Iwona Solarska ◽  
Joanna Niesiobedzka-Krezel ◽  
Ilona Seferynska ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Mutation Frequency ◽  
Kinase Domain ◽  
Advisory Committees ◽  
Secondary Resistance ◽  
Genetic Aberrations ◽  
Paired Samples ◽  
Clinical Resistance

Clinical resistance to tyrosine kinase inhibitors (TKI) remains a significant problem in the therapy of patients with chronic myeloid leukemia (CML). Although BCR-ABL1-kinase domain mutations are the major cause of resistance to TKI, some patients manifest primary or develop secondary resistance to TKI without detectable BCR-ABL1 mutations. We aimed to assess the prevalence of additional gene mutations in a group of 50 patients with primary (n = 26) or secondary resistance (n = 24) to TKI, in most cases to imatinib (n = 49) and in one to dasatinib. We employed ~1000 genes custom target enrichment kit and next-generation sequencing on Illumina platform, as well as Sanger sequencing. In 21 patients, we were able to match and analyze paired samples collected at diagnosis (before treatment) and at the time of resistance and in five other cases we analyzed additional samples collected later during TKI-resistant chronic phase or in blast crisis. The most frequent genetic aberrations detected at the time of TKI-resistance were mutations in ASXL1 and BCR-ABL1 kinase domain coding sequence, present in 28% (14/50) and 26% (13/50) of patients, respectively. Both genes were mutated in 12% of patients (6/50), while 30% (15/50) had either ASXL1 or BCR-ABL1 mutations alone. Non-recurrent genetic aberrations in other genes were also noted in single patients (e.g. DNMT3A mutations). According to COSMIC database, all but three ASXL1 mutations detected in this study were previously described in hematologic malignancies and all (including the novel ones) are predicted to introduce stop codons or cause frameshifts in codon range of 512-943, thus truncating the protein before the C-terminal PHD domain. Among patients with available paired samples three had more than one ASXL1 mutation at various time points and in all of them we observed dynamics of specific ASXL1 mutations, related partially to the leukemic cell content in the sample but also providing evidence of clonal evolution (Table 1). In most of patients with concurrent ASXL1 and BCR-ABL1 mutations, we observed that both mutations were present with similar variant allele frequency (VAF), suggesting that ASXL1 mutations occur in Philadelphia-positive leukemic clones (Table 2). ASXL1 mutation frequency was significantly higher in TKI-resistant patients, than in our previously characterized group of CML patients without resistance, who achieved major molecular response (28% ; 14/50 vs 5.6% ; 2/36, respectively, p = 0.0105, Fisher exact test). All ASXL1-mutated patients with secondary (n = 1) or primary resistance (n = 5) for whom diagnostic sample was available, carried ASXL1 mutation also at the time of diagnosis. No significant difference in mutation frequency was found between patients with primary and secondary resistance (ASXL1 mutation, 26.9% vs 29.2% ; BCR-ABL1 mutation, 15.4% vs 37.5%). Our results provide evidence that preexisting ASXL1 mutations in BCR-ABL1-positive leukemic clone present at diagnosis may have impact on clinical response to imatinib and may be useful in assessing the risk of treatment failure. Disclosures Niesiobedzka-Krezel: Novartis: Honoraria. Seferynska:Novartis: Honoraria. Gora Tybor:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sacha:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

scholarly journals ID: 2036 Next-generation sequencing to evaluate frequency of BCR-ABL1 kinase domain Imatinib-resistance mutations

2017 ◽  
Vol 4 (S) ◽  
pp. 67
Author(s):  
Chinh Q. Duong ◽  
Trang T. Nguyen ◽  
Lam V. Nguyen ◽  
Huy Q. Pham ◽  
Hien T. T. Trinh ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Next Generation Sequencing ◽  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Fusion Gene ◽  
Kinase Domain ◽  
Imatinib Resistance ◽  
Kinase Domain Mutation ◽  
Generation Sequencing

Chronic myeloid leukemia is a clonal myeloproliferative neoplasm, characterized by the presence of chromosomal translocation t(9; 22)(q34; q11). This is found in over 95% of the cases and results in the BCR-ABL1 fusion gene with high tyrosine kinase activity. During the last decades, imatinib and other generation of tyrosine kinase inhibitors have been used effectively for target therapy of the disease. However, many of the drug resistance cases have been reported recently, due to the mutation within kinase domain of the BCR-ABL1 fusion gene. In this work, we performed a retrospective study of 141 imatinib-resistance chronic myeloid leukemia patients to analyze kinase domain mutation by deep sequencing. Another group of 20 untreated patients were added as control. RNA from bone marrow cells was extracted and deeply sequenced utilizing Illumina MiSeq. Bioinformatics pipeline was applied for variant calling and annotation. And the Sanger sequencing was used to validate those mutations. The results showed that nearly one-fourth of patients harboring mutations that resist to Imatinib, among those, Y253F/H, M351T, G250E, F359V/I and M244V were the most frequent mutations. There were also a number of samples harboring multiple substitutions and new variations. Thus, Next-generation sequencing could be the sensitive and effective method to detect kinase domain mutation and our results could provide further information about the drug-resistance mutation in chronic myeloid leukemia.

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