MicroRNAs that affect the Fanconi Anemia/BRCA pathway are downregulated in imatinib-resistant chronic myeloid leukemia patients without detectable BCR-ABL kinase domain mutations

Sze Wei Yap, Z. A. Norziha, A. Simbun, Nor Rafeah Tumian, S. K. Cheong, Leong Chooi Fun, Chieh Lee Wong

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Chronic myeloid leukemia (CML) patients who do not achieve landmark responses following treatment with imatinib mesylate (IM) are considered IM-resistant. Although IM-resistance can be due to BCR-ABL kinase domain (KD) mutations, many IM-resistant patients do not have detectable BCR-ABL KD mutations. MicroRNAs (miRNAs) are short non-coding RNAs that control gene expression. To investigate the role of miRNAs in IM-resistance, we recruited 8 chronic phase CML patients with IM-resistance who tested negative for BCR-ABL KD mutations and 2 healthy normal controls. Using miRNA sequencing, we identified 54 differentially expressed miRNAs; 43 of them downregulated. The 3 most differentially downregulated miRNAs were miR-146a-5p, miR-99b-5p and miR-151a-5p. Using real-time quantitative reverse transcriptase-polymerase chain reaction, the expression patterns of the 3 miRNAs were validated on the same cohort of 8 patients in addition to 3 other IM-resistant CML patients. In-silico analysis showed that the predicted gene targets are ATRIP, ATR, WDR48, RAD51C and FANCA genes which are involved in the Fanconi Anemia/BRCA pathway. This pathway regulates DNA damage response (DDR) and influences disease response to chemotherapy. Thus it is conceivable that DDR constitutes a key component in IM-resistance. Further research is needed to elucidate miRNA modulation of the predicted gene targets.

Original languageEnglish
Pages (from-to)32-40
Number of pages9
JournalLeukemia Research
Volume59
DOIs
Publication statusPublished - 1 Aug 2017

Fingerprint

Fanconi Anemia
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
MicroRNAs
Phosphotransferases
Down-Regulation
Mutation
DNA Damage
Genes
Leukemia, Myeloid, Chronic Phase
Untranslated RNA
Imatinib Mesylate
Reverse Transcriptase Polymerase Chain Reaction
Computer Simulation
Gene Expression
Drug Therapy

Keywords

  • BRCA pathway
  • Chronic myeloid leukemia
  • Fanconi anemia
  • Imatinib resistance
  • miRNA-seq

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

MicroRNAs that affect the Fanconi Anemia/BRCA pathway are downregulated in imatinib-resistant chronic myeloid leukemia patients without detectable BCR-ABL kinase domain mutations. / Yap, Sze Wei; Norziha, Z. A.; Simbun, A.; Tumian, Nor Rafeah; Cheong, S. K.; Chooi Fun, Leong; Wong, Chieh Lee.

In: Leukemia Research, Vol. 59, 01.08.2017, p. 32-40.

Research output: Contribution to journalArticle

@article{345c4699851b4b9d9d3f72f4f7e7cbd6,
title = "MicroRNAs that affect the Fanconi Anemia/BRCA pathway are downregulated in imatinib-resistant chronic myeloid leukemia patients without detectable BCR-ABL kinase domain mutations",
abstract = "Chronic myeloid leukemia (CML) patients who do not achieve landmark responses following treatment with imatinib mesylate (IM) are considered IM-resistant. Although IM-resistance can be due to BCR-ABL kinase domain (KD) mutations, many IM-resistant patients do not have detectable BCR-ABL KD mutations. MicroRNAs (miRNAs) are short non-coding RNAs that control gene expression. To investigate the role of miRNAs in IM-resistance, we recruited 8 chronic phase CML patients with IM-resistance who tested negative for BCR-ABL KD mutations and 2 healthy normal controls. Using miRNA sequencing, we identified 54 differentially expressed miRNAs; 43 of them downregulated. The 3 most differentially downregulated miRNAs were miR-146a-5p, miR-99b-5p and miR-151a-5p. Using real-time quantitative reverse transcriptase-polymerase chain reaction, the expression patterns of the 3 miRNAs were validated on the same cohort of 8 patients in addition to 3 other IM-resistant CML patients. In-silico analysis showed that the predicted gene targets are ATRIP, ATR, WDR48, RAD51C and FANCA genes which are involved in the Fanconi Anemia/BRCA pathway. This pathway regulates DNA damage response (DDR) and influences disease response to chemotherapy. Thus it is conceivable that DDR constitutes a key component in IM-resistance. Further research is needed to elucidate miRNA modulation of the predicted gene targets.",
keywords = "BRCA pathway, Chronic myeloid leukemia, Fanconi anemia, Imatinib resistance, miRNA-seq",
author = "Yap, {Sze Wei} and Norziha, {Z. A.} and A. Simbun and Tumian, {Nor Rafeah} and Cheong, {S. K.} and {Chooi Fun}, Leong and Wong, {Chieh Lee}",
year = "2017",
month = "8",
day = "1",
doi = "10.1016/j.leukres.2017.05.015",
language = "English",
volume = "59",
pages = "32--40",
journal = "Leukemia Research",
issn = "0145-2126",
publisher = "Elsevier Limited",

}

TY - JOUR

T1 - MicroRNAs that affect the Fanconi Anemia/BRCA pathway are downregulated in imatinib-resistant chronic myeloid leukemia patients without detectable BCR-ABL kinase domain mutations

AU - Yap, Sze Wei

AU - Norziha, Z. A.

AU - Simbun, A.

AU - Tumian, Nor Rafeah

AU - Cheong, S. K.

AU - Chooi Fun, Leong

AU - Wong, Chieh Lee

PY - 2017/8/1

Y1 - 2017/8/1

N2 - Chronic myeloid leukemia (CML) patients who do not achieve landmark responses following treatment with imatinib mesylate (IM) are considered IM-resistant. Although IM-resistance can be due to BCR-ABL kinase domain (KD) mutations, many IM-resistant patients do not have detectable BCR-ABL KD mutations. MicroRNAs (miRNAs) are short non-coding RNAs that control gene expression. To investigate the role of miRNAs in IM-resistance, we recruited 8 chronic phase CML patients with IM-resistance who tested negative for BCR-ABL KD mutations and 2 healthy normal controls. Using miRNA sequencing, we identified 54 differentially expressed miRNAs; 43 of them downregulated. The 3 most differentially downregulated miRNAs were miR-146a-5p, miR-99b-5p and miR-151a-5p. Using real-time quantitative reverse transcriptase-polymerase chain reaction, the expression patterns of the 3 miRNAs were validated on the same cohort of 8 patients in addition to 3 other IM-resistant CML patients. In-silico analysis showed that the predicted gene targets are ATRIP, ATR, WDR48, RAD51C and FANCA genes which are involved in the Fanconi Anemia/BRCA pathway. This pathway regulates DNA damage response (DDR) and influences disease response to chemotherapy. Thus it is conceivable that DDR constitutes a key component in IM-resistance. Further research is needed to elucidate miRNA modulation of the predicted gene targets.

AB - Chronic myeloid leukemia (CML) patients who do not achieve landmark responses following treatment with imatinib mesylate (IM) are considered IM-resistant. Although IM-resistance can be due to BCR-ABL kinase domain (KD) mutations, many IM-resistant patients do not have detectable BCR-ABL KD mutations. MicroRNAs (miRNAs) are short non-coding RNAs that control gene expression. To investigate the role of miRNAs in IM-resistance, we recruited 8 chronic phase CML patients with IM-resistance who tested negative for BCR-ABL KD mutations and 2 healthy normal controls. Using miRNA sequencing, we identified 54 differentially expressed miRNAs; 43 of them downregulated. The 3 most differentially downregulated miRNAs were miR-146a-5p, miR-99b-5p and miR-151a-5p. Using real-time quantitative reverse transcriptase-polymerase chain reaction, the expression patterns of the 3 miRNAs were validated on the same cohort of 8 patients in addition to 3 other IM-resistant CML patients. In-silico analysis showed that the predicted gene targets are ATRIP, ATR, WDR48, RAD51C and FANCA genes which are involved in the Fanconi Anemia/BRCA pathway. This pathway regulates DNA damage response (DDR) and influences disease response to chemotherapy. Thus it is conceivable that DDR constitutes a key component in IM-resistance. Further research is needed to elucidate miRNA modulation of the predicted gene targets.

KW - BRCA pathway

KW - Chronic myeloid leukemia

KW - Fanconi anemia

KW - Imatinib resistance

KW - miRNA-seq

UR - http://www.scopus.com/inward/record.url?scp=85019904024&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85019904024&partnerID=8YFLogxK

U2 - 10.1016/j.leukres.2017.05.015

DO - 10.1016/j.leukres.2017.05.015

M3 - Article

C2 - 28544907

AN - SCOPUS:85019904024

VL - 59

SP - 32

EP - 40

JO - Leukemia Research

JF - Leukemia Research

SN - 0145-2126

ER -