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Front. Biol.    2016, Vol. 11 Issue (5) : 404-411    https://doi.org/10.1007/s11515-016-1423-1
RESEARCH ARTICLE
Incidence of T315I mutation in BCR/ABL-positive CML and ALL patients
Fatemeh Norozi1,Javad Mohammadi-asl2,Tina Vosoughi1,Mohammad Ali Jalali Far1,Amal Saki Malehi1,Najmaldin Saki1()
1. Health Research Institute, Thalassemia and Hemoglobinopathy Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
2. Department of Medical Genetics, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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Abstract

OBJECTIVES: Targeted therapy of Philadelphia-positive ALL and CML patients using imatinib (IM) has caused significant changes in treatment course and has increased the survival of patients. A small group of patients show resistance to IM. Acquired mutations in tyrosine kinase domain of BCR-ABL protein are a mechanism for development of resistance. T315I is one of the most common acquired mutations in this domain, which occurs in ATP binding site and inhibits the formation of hydrogen bond with IM. The aim of this study was to evaluate the prevalence of this mutation in BCR/ABL-positive CML and ALL patients.

METHODS: To conduct this study, 60 BCR-ABL-positive patients (including 50 CML and 10 ALL patients) who were subject to treatment with IM were selected. After taking the samples, presence of T315I mutation was assessed using ARMS-PCR on cDNA and its polymorphism was evaluated by sequencing.

RESULTS: The results showed that among 60 patients, only three patients had T315I mutation, which was detected using ARMS technique. The three patients bearing mutation were afflicted with CML and no significant association was found between blood parameters with duration of treatment in presence of mutation.

CONCLUSIONS: The mutation was found in three CML patients, which indicated lower likelihood and diagnostic value of this mutation in ALL patients. Given the negative direct sequencing results in T315I patients, it can be concluded that ARMS-PCR is a more sensitive technique when the number of cancer cells is low in patients during treatment.
Keywords BCR-ABL      T315I mutation      imatinib      CML      ALL     
Corresponding Author(s): Najmaldin Saki   
Online First Date: 08 October 2016    Issue Date: 04 November 2016
 Cite this article:   
Fatemeh Norozi,Javad Mohammadi-asl,Tina Vosoughi, et al. Incidence of T315I mutation in BCR/ABL-positive CML and ALL patients[J]. Front. Biol., 2016, 11(5): 404-411.
 URL:  
https://academic.hep.com.cn/fib/EN/10.1007/s11515-016-1423-1
https://academic.hep.com.cn/fib/EN/Y2016/V11/I5/404
Fig.1  (A) The formation of the Bar-Abl fusion gene. (B) The most common mutations in BCR/ABL tyrosine kinase domain. (A) Depending on the locus where the break occurs in Bcr gene, chimeric Bcr-Abl gene bears two, three or even more exons than normal gene, which results in the formation of chimeric proteins of different sizes. (B) Several mutations occur in Bcr-Abl kinase domain. The most common sites include P-loop (codons 244-256), ATP binding site (codons 315 and F317), catalytic domain (codons 350-363) and activation loop (codons 381-407). T315I mutation occurs in ATP binding site where IM is found, causing resistance to treatment of patients with IM.
CML ALL p-value
Sex Male 48.0% 80.0% -
Female 52.0% 20.0% -
Age 45.19 (16.0-75.0) 17.25 (3.0-50.0) -
WBC1* 42.3 (5.30-220.4) 20.0 (10.20-119.70) 0.82
WBC2** 6.19 (3.35-19.2) 8.3 (3.5-10.3) 0.249
Hb1* 10.65 (8.1-19.1) 10.7 (8.5-13.0) 0.654
Hb2** 11.6 (8.0-16.4) 10.0 (8.4-11.8) 0.019
PLT1* 389.0 (168.0-2166.0) 102.0 (30.0-274.0) 0.0001
PLT2** 189.0 (59.0-1289.0) 111.0 (60.0-297.0) 0.145
Organomegaly No organomegaly 62.0% 55.6% -
Hepatomegaly 0.0% 11.1% -
Splenomegaly 30.0% 11.1% -
Hepato-Splenomegaly 8.0% 22.2% -
Therapy duration >1 year 51.2% 100.0% -
1 year 31.7% 0.0% -
<1 year 17.1% 0.0% -
Therapy response Optimal 52.3% 90.0% -
Failure 40.9% 10.0% -
Warning 6.8% 0.0% -
Tab.1  Clinical characteristics of patients
Group Total
CML ALL
T315I
mutation		 Negative (47)
94.0%		 (10)
100.0%		 (57)
95.4%
Positive (3)
6.0%		 (0)
0.0%		 (3)
4.6%
Total (50)
100.0%		 (10)
100.0%		 (60)
100.0%
Tab.2  The T315I mutation rate in BCR/ABL positive patients
T315I????? Total
Negative Positive
Duration >1 year 58.3% 100.0% 60.8%
<1 year 14.6% 0.0% 13.7%
1 year 27.1% 0.0% 25.5%
Total 100.0% 100.0% 100.0%
Chisquare(p-value) 2.056 (0.418)
Tab.3  T315I mutation and during treatment relationship in CML patients
T315I Total
Negative Positive
Response Optimal (37)
58.8%		 (2)
66.7%		 59.3%
Failure (17)
35.3%		 (1)
33.3%		 35.2%
Warning (3)
5.9%		 (0)
0.0%		 5.6%
Total 100.0% 100.0% 100.0%
Chisquare (p-value) 0.209 (1.00)
Tab.4  T315I mutation and responses to treatment relationship in CML patients
Fig.2  Evaluation of T315I mutation by direct sequencing technique in BCR-ABL-positive patients.
Fig.3  Evaluation of T315I mutation by ARMS-PCR techniques in BCR-ABL-positive patients.
Fig.4  Activation of different signaling molecules by BCR-ABL fusion protein. BCR-ABL protein activates several signaling pathways that enhance cell proliferation and genetic instability, inhibit apoptosis and reduce cell adhesion. The most important signaling molecules activated by BCR-ABL fusion protein include Myc, Ras, MAP/ERK, JAK/STAT, NFκB, PI-3kinase and c-Jun. Therefore, BCR-ABL can act as an oncoprotein via activation of these signaling pathways.
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