A Study on BCR-ABL Kinase Domain Mutations in Chronic Myeloid Leukemia from Western India

  1. Pankaj Gadhia ,
  2. Jessica Jeejan ,
  3. Vishma Shah ,
  4. Monika Patel ,
  5. Salil Vaniawala

Vol 6 No 3 (2021)

DOI 10.31557/apjcb.2021.6.3.225-227

Abstract

Background: BCR-ABL kinase domain(KD) mutations accounts for 60-80% of Imatinib resistance in chronic myeloid leukemia (CML) – chronic phase (CP). Patients with CML who are receiving imatinib treatment, a mutation analysis is required to find out the resistance of imatinib as per European Leukemia Net (ELN) criteria. The present study was carried out to assess for different types of mutations responsible for resistance of imatinib treatment from Western India.
Methods: In a retrospective study, the patients who were tested for imatinib resistance were analysed for IRMA testing using direct sequencing of BCR-ABL transcript by Sanger method.
Results: A total of 215 patients were tested for Imatinib resistance analysis (IRMA), of which 45 (20.93%) had detectable mutations. The highest frequency of mutation recorded at T315I amino acids site, followed by M244V and G250E sites.
Conclusion: The patients who were tested for IRMA showed 20.93 % positive mutations with reference to its resistance are discussed.


 

Introduction

Chronic myeloid leukemia (CML) is characterized by positive Philadelphia (Ph+ ) chromosome. There is reciprocal translocation of t (9;22) (q34;q11) [1] which results in the head to tail fusion of breakpoint cluster region (BCR) gene on chromosome 22q11 with ABL1 (Abelson murine leukemia virus) gene located on chromosome 9q34 creating BCR-ABL1 oncogene. CML has three clinical phases namely chronic, accelerated and blast crises.

The standard treatment of CML-CP is Imatinib mesylate first generation tyrosine kinase inhibitor. Imatinib (400 mg) used as a first-line drug to treat CML which inhibits the abnormal bcr-abl tyrosine kinase inhibitor created by Philadelphia (Ph+ ) positive chromosome translocation abnormality [2, 3].

It is well established that imatinib still remains gold standard for treatment of CML especially in low income group countries. Although Imatinib is an important treatment of CML but 50-90% of imatinib resistance observed for bcr-abl kinase domain (KD).

Mutation [4]. Therefore, the present study was aimed to assess types of mutations responsible for resistance to imatinib in CML patients of Western India.

Materials and Methods

The samples of patients, who were imatinib resistant were admitted and analysed at S.N.Gene Laboratory and Research Centre, Surat, India. A total of 215 samples received for IRMA analysis were collected between October, 2020 and July, 2021 (ten months) from different parts of Western India. The inclusion criteria were suspected Philadelphia positive patients and exclusion criteria were Philadelphia negative patients. The informed consent was taken from each patients. The IRMA analysis was carried out with Sanger’s sequencing method. The results were analysed using BLAST software from NCBI.

Results

A total of 215 patients were screened, of which 148 were males and 67 were females.

The age varies from 4 to 74 years. Among 215 patients, 170 did not have any type of mutations (Table 1).

Table 1. Frequency Analysis of KD Mutations.

Number of patients screened 215
Mutation identified in (%) 20.93
Point mutation seen 45
Point mutation seen Number of patients
T315I 14
M244V 07
G250E 04
F317C 03
F359V 02
D276G 02
H396R 02
F359C 02
F359I 01
S417F 01
M237V 01
M255V 01
E255K 01
Y253H 01
E450K 01
E453V 01
E462K 01

The 45 patients who were positive for mutations showed a higher frequency of mutation at T315I, M244V and G250E. In addition, Table 2 shows a list of mutations found in the present study which were resistance to Imatinib, Dasatinib, Nilotinib, Bosutinib and Ponatinib based on the integration published studies between 2001 and 2018 [5].

Table 2. List of BCR-ABL1KD mutations resistance (+) to Imatinib, Dasatinib, Nilotinib, Bosutinib and Ponatinib based on Integration of Published Study (2001-2018) [5].

Mutation Imatinib Dasatinib Nilotinib Bosutinib Ponatinib
T315I + + + + +
M244V + --- --- --- ---
F359I + --- + --- ---
F359C + --- + --- ---
M237V + --- --- --- ---
F317C + + --- --- ---
G250E + --- --- --- ---
F359V + --- + --- ---
S417F + --- --- --- ---
D276G + --- --- --- ---
E255K + --- + + ---
Y253H + --- + --- ---
E450K + --- --- --- ---
E255V + --- + + ---
H396R + --- --- --- ---
E453V + --- --- --- ---
E462K + --- --- --- ---

Discussion

Imatinib has shown a success in the treatment of CML in the last few years, there have been reports about Imatinib resistance in overall outcome of disease. The aim of the present study was to investigate the presence of ABL-KD domain mutation in Philadelphia positive (Ph+) cases of CML patients in population of Western India. Of 215 CML Philadelphia positive patients, 45 (20.93%) showed mutations detected by IRMA. Our study is partly in agreement with reported studies in India. Mallekavu et al.[6] have reported a total cases 120, of which, 36 (30%) had detectable mutations. In another study conducted by Rajappa et al. [7] has reported that out of 90 patients, 29 (32.2%) had detectable mutations. On the contrary, a considerably higher percentage of mutations (43%) was reported in the GIMEMA study from Italy [8].

In the present study, we observed a higher frequency of mutations at amino acids T315I followed by M244V and G250E which was in contrast to the study reported by Mallekavu et al. [6] except for a high frequency of mutation at amino acid T315I. We have also compared BCR-ABL KD mutations resistance to Imatinib, Dasatinib, Nilotinib, Bosutinib and Ponatinib based on the integration of published studies between 2001 and 2018 where T315I mutation was resistance to all three generation drugs. The lower percentage of mutations rate (20.93%) was found in the present study could attribute to samples received was primarily of CP-CML.

In conclusion, the patients who were tested for IRMA showed 20.93% positive mutations. The highest frequency was noted in T315I mutation in imatinib treated patients. This will give an indication to clinicians to reconsider therapeutic strategy or go for bone-marrow transplantation.

Acknowledgements

Authors would like to thank Tushar Kachhadiya for his help.

Conflict of interest

Authors declare no conflict of interest.

References


  1. A New Consistent Chromosomal Abnormality in Chronic Myelogenous Leukaemia identified by Quinacrine Fluorescence and Giemsa Staining ROWLEY JANET D.. Nature.1973;243(5405). CrossRef
  2. Hematologic and Cytogenetic Responses to Imatinib Mesylate in Chronic Myelogenous Leukemia Kantarjian Hagop, Sawyers Charles, Hochhaus Andreas, Guilhot Francois, Schiffer Charles, Gambacorti-Passerini Carlo, Niederwieser Dietger, Resta Debra, Capdeville Renaud, Zoellner Ulrike, Talpaz Moshe, Druker Brian. New England Journal of Medicine.2002;346(9). CrossRef
  3. Chronic myeloid leukemia: current treatment options Goldman John M., Druker Brian J.. Blood.2001;98(7). CrossRef
  4. Dynamics of BCR-ABL mutated clones prior to hematologic or cytogenetic resistance to imatinib Ernst T., Erben P., Muller M. C., Paschka P., Schenk T., Hoffmann J., Kreil S., La Rosee P., Hehlmann R., Hochhaus A.. Haematologica.2008;93(2). CrossRef
  5. Next-generation sequencing for BCR-ABL1 kinase domain mutation testing in patients with chronic myeloid leukemia: a position paper Soverini Simona, Abruzzese Elisabetta, Bocchia Monica, Bonifacio Massimiliano, Galimberti Sara, Gozzini Antonella, Iurlo Alessandra, Luciano Luigiana, Pregno Patrizia, Rosti Gianantonio, Saglio Giuseppe, Stagno Fabio, Tiribelli Mario, Vigneri Paolo, Barosi Giovanni, Breccia Massimo. Journal of Hematology & Oncology.2019;12(1). CrossRef
  6. Imatinib resistance mutation analysis: experience from a tertiary oncology center Suresh babu Mallekavu, Sirsath Nagesh, Lakshmaiah Kuntejowdahalli, Babu Govind, Martahalli Suresh, Dasappa Lokanatha. International Journal of Cancer Therapy and Oncology.2015;3(2). CrossRef
  7. Kinase domain mutations and responses to dose escalation in chronic myeloid leukemia resistant to standard dose imatinib mesylate Rajappa Senthil, Mallavarapu Krishna Mohan, Gundeti Sadashivudu, Paul Tara Roshni, Jacob Rachel Thomas, Digumarti Raghunadharao. Indian Journal of Medical and Paediatric Oncology.2013;34(03). CrossRef
  8. ontribution of ABL kinase domain mutations to Imatinib resistance in different subsets of Philadelphia-positive patients. By the GIMEMA working party on chronic myeloid leukemia Soverini S, Calarossi S, Gnani A, et al . Clin Can Res.2006;12:7374-7379.

Copyright

© Asian Pacific Journal of Cancer Biology , 2021

Author Details

Pankaj Gadhia
S.N.Gene Pvt. Ltd and Research Centre
pankajkgadhia@gmail.com

Jessica Jeejan
Department of Biochemistry and Biotechnology, St. Xavier College, Ahmedabad, India.

Vishma Shah
S.N.Gene Laboratory and Research Centre, Surat, India

Monika Patel
S.N.Gene Laboratory and Research Centre, Surat, India

Salil Vaniawala
S.N.Gene Laboratory and Research Centre, Surat, India

How to Cite

1.
Gadhia P, Jeejan J, Shah V, Patel M, Vaniawala S. A Study on BCR-ABL Kinase Domain Mutations in Chronic Myeloid Leukemia from Western India. apjcb [Internet]. 11Oct.2021 [cited 29Nov.2021];6(3):225-7. Available from: http://waocp.com/journal/index.php/apjcb/article/view/740

 


 


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