title: Down-regulation of miR-199b associated with imatinib drug resistance in 9q34.1 deleted BCR/ABL positive CML patients.
abstract: Chronic myeloid leukemia (CML) occurs due to t(9,22) (q34;q11) and molecularly BCR/ABL gene fusion. About 15-18% Philadelphia positive CML patients have gene deletions around the translocation breakpoints on 9q34.1. The microRNAs (miRNAs), namely miR-219-2 and miR-199b, centromeric to the ABL1 gene are frequently lost in CML patients. We have designed a study to determine miR-219-2 and miR-199b expression levels which would help to understand the prognosis of imatinib therapy. A total of 150 CML patients were analyzed to identify 9q deletion. Fluorescent in-situ hybridization (FISH) was performed using BCR/ABL dual color, dual fusion probe to study the signal pattern and BAC probes for miR-199b and miR-219-2 (RP11-339B21 and RP11-395P17) to study the miRNA deletions. The expression level of miRNA was analyzed by real-time polymerase chain reaction (RT-PCR). FISH analysis revealed 9q34.1 deletion in 34 (23%) CML patients. The deletions were not detected using BAC probes for miRNAs in 9q deleted patients. The expression analysis showed down-regulation of miR-199b and miR-219-2 in the 9q deleted patients (34 CML) as compared to a pool of patients without deletion. However, miR-199b (9q34.11) was significantly (p=0.001) down-regulated compared to miR-219-2. The follow-up study showed that the miR-199b was found to be strongly associated with imatinib resistance, as 44.11% patients showed resistance to imatinib therapy. Hence, the deletion in 9q34.1 region (ABL) plays an important role in disease pathogenesis. Eventually, miRNAs can provide new therapeutic strategies and can be used as a prognostic indicator.
authors.affiliation: Department of Cytogenetics, National Institute of Immunohaematology, 13th Floor, New Multistoried Building, KEM Hospital Campus, Parel, Mumbai 400012, India.
authors.forename: Dolly
authors.initials: D
authors.lastname: Joshi
authors.affiliation: Department of Haematology, 10th Floor, New Multistoried Building, KEM Hospital, Parel, Mumbai 400012, India.
authors.forename: S
authors.initials: S
authors.lastname: Chandrakala
authors.affiliation: Department of Cytogenetics, National Institute of Immunohaematology, 13th Floor, New Multistoried Building, KEM Hospital Campus, Parel, Mumbai 400012, India.
authors.forename: Seema
authors.initials: S
authors.lastname: Korgaonkar
authors.affiliation: Department of Cytogenetics, National Institute of Immunohaematology, 13th Floor, New Multistoried Building, KEM Hospital Campus, Parel, Mumbai 400012, India.
authors.forename: Kanjaksha
authors.initials: K
authors.lastname: Ghosh
authors.affiliation: Department of Cytogenetics, National Institute of Immunohaematology, 13th Floor, New Multistoried Building, KEM Hospital Campus, Parel, Mumbai 400012, India. Electronic address: vbaburao@hotmail.com.
authors.forename: Babu Rao
authors.initials: BR
authors.lastname: Vundinti
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001549:Benzamides / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D022202:Chromosomes, Artificial, Bacterial; D002899:Chromosomes, Human, Pair 9; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D000068877:Imatinib Mesylate; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D010879:Piperazines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D001549:Benzamides; C578248:MIRN219 microRNA, human; D035683:MicroRNAs; D010879:Piperazines; D011743:Pyrimidines; C531408:mirn199 microRNA, human; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl
keywords: 9q deletion; Chronic myeloid leukemia; Real time PCR; miR-199b; miR-219-2