Correspondence Author: Phan Chin Lee
Address: Hospital Ampang, Makmal Klinikal Hematologi, Jalan Mewah Utara, Pandan Mewah, 68000
Ampang, Selangor Darul Ehsan
e-mail: cuapcl@hotmail.com
Authors
Zubaidah Zakaria1, Chin Lee Phan 2,3, Kah Yuen Lam1, Puteri Megat Baharuddin1, Ong Tee Chuan2, Azli Ismail1,
Nor Asiah Muhamad1, Ching Ching Ng3, Subramanian Yegappan2, Kian Meng Chang2
1
Institute for Medical Research, Cancer Research Center (CaRC), 50800, Kuala Lumpur, Malaysia
Clinical Hematology Laboratory, Hospital Ampang Selangor, Malaysia
3
Institute of Biological Sciences, Faculty of Science Building, University of Malaya, 50603 Kuala Lumpur,
Malaysia
2
COMMONLY GENE DELETED IN ADULT BCR-ABL1 POSITIVE ACUTE LYMPHOBLASTIC
LEUKEMIA PATIENTS
Introduction
Philadelphia chromosome (Ph) / BCR-ABL–positive acute lympoblastic leukemia (ALL) is the largest genetically
defined subtype in adult ALL. This patient is frequently treated with intensive chemotherapy followed by
hematopoietic stem cell transplantation. However, despite of this intensive therapy , the prognosis of Ph-positive
adult ALL remains poor. Our aim of this study was to use Multiplex Ligation-dependent Probe Amplification
(MLPA) to characterize the frequency of CNAs in B-lineage adult Ph-positive (Ph+)ALL.
Materials and Methods
Karyotype, Genomic DNA and RNA were extracted from bone marrow or peripheral blood samples at initial
diagnosis or relapsed using standard methods in Hospital Ampang. MLPA assays (MRC-Holland, The Netherlands)
were performed for the following genes: IKZF1, CDKN2A/B, PAX5, EBF1, ETV6, BTG1, RB1, and genes within
PAR1: CRLF2, CSF2RA, IL3RA, using the SALSA MLPA P335-B1 ALL-IKZF1P335. A deletion of IKZF1 was
confirmed and further characterized by the P202 for IKZF1 SALSA MLPA kits.
Results
In total, 47 patients (Female=27, Male=20) with BCR-ABL1 positive or Ph+ were included in this study. Range of
age is 14-71 years. Approximately 51.1% (24/47) of these patients was identify having e1a2 transcripts, 27.7%
(13/47) e13a2 and 21.3% (10/47) e14a2 fusion transcripts. Additional chromosomal abnormalities were present in
13 (68.4%) of the 19 patients in whom cytogenetic analysis was successful. Incidence of CNAs tested by MLPA for
targeted gene aberrations showed 83% (39/47) of patients revealed genes aberrations, which showed at 17 (34%)
patients had one, 5 (10.6%) had two, 6 (12.8%) had three and 11 (23.4%) had four or more deletions. Total
number of genes abnormalities is 93. No CNAs were identified in 8 (17.0%) of the patients and three of the patients
harbored only a deletion of CDK2A/B locus and one of these patients also showed addition BTG1 deleted,
heterozygous duplications of EBF1 locus and PAR1 gene locus. Concurrent deletions of IKZF1, CDKN2A/B, PAX5
or BTG1 locus were detected in 12 and 4 patients respectively. Overall, most common deleted gene identified in this
study were IKZF1 (n=36, 76.6%) follow by CDKN2A/B (n=17, 36.2%), PAX5 (n=15, 31.9%), RB1 (n=8, 17.0%),
BTG1 (n=8, 17.0%), EBF1 (n=4, 8.5%), ETV6 (n=2, 4.3%), Xp22.33 heterozygous duplication (n=2, 4.3%) and
CRLF2 heterozygous duplication (n=1, 21.1%). Of 36 patient with IKZF1 deletion, the most frequent. IKZF1
deletion regions involved 36.1% (n=13) at exon 4-7, 16.7%, 30.6% involved whole gene loss of IKZF1 (n=11), and
8.3% each at exon 1-2 and exon 1-3 respectively.
Conclusions
In conclusion, using MLPA analysis, we showed that Intragenic IKZF1 deletions are highly occurrence in adult Phpositive ALL and most frequently involved exon 4 to 7 follow by whole gene loss of IKZF1. Patients with partial
IKZF1 gene deletions have been reported have a significantly higher probability of relapse than those with whole
gene loss. Genomic lesions other than IKZF1 such as CDKN2 and PAX5 can serve as prognostic factor to better
understanding the prognostic value these genes in disease prognosis in adult Ph+ ALL patients.
Supported by the PTK grants from ministry of Health. Project code: 12-040 ; NMRR-12-1287-13936
Disclosures: No relevant conflicts of interest to declare.