Genomic and transcriptomic profiles and in vitro resistance to mitoxantrone and idarubicin in pediatric acute leukemias.
BACKGROUND
A major problem in the treatment of leukemia is the development of drug resistance to chemotherapeutic agents.


METHODS
To determine the ex vivo drug resistance profile to anthracyclines, an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazoliumbromide (MTT) cytotoxicity assay was performed on mononuclear cells obtained from 155 patients with acute lymphoblastic leukemia (ALL) or acute myeloblastic leukemia (AML). Gene expression profiles (for 51 patients with ALL and 16 with AML) were prepared on the basis of cRNA hybridization to oligonucleotide arrays of the human genome (Affymetrix). Hierarchical clustering, assignment location and biological function were investigated during the correlation analysis for identified probe sets. Comparative genomic hybridization (CGH) array profiles (34 patients with ALL and 12 with AML) were prepared on the basis of DNA hybridization to oligonucleotide arrays of the human genome (Agilent). The validation of the array results was performed by a quantitative reverse transcriptase polymerase chain reaction.


RESULTS
The collected expression and CGH microarray experiment results indicate that the ITGB2, SCL6A7, CASP1 and DUSP genes may comprise a resistance marker for acute leukemia cells correlated with anthracyclines. Moreover, there were also identified chromosome rearrangements associated with drug resistance, such as del5q32-35.3 and amp8p12-p11.21. Precise genes, as well as genome aberrations, might be classified as targets in therapy.


CONCLUSIONS
In AML, the resistance of blasts to idarubicin and mitoxantrone may reflect an impaired integrin pathway. In ALL, the development of resistance is caused by the inhibition of B and T cell activation. Copyright © 2016 John Wiley & Sons, Ltd.
Department of Plant Physiology and Biotechnology, Nicolaus Copernicus University, Torun, Poland.|Centre for Modern Interdisciplinary Technologies, Nicolaus Copernicus University, Torun, Poland.
Joanna
J
Laskowska
Department of Plant Physiology and Biotechnology, Nicolaus Copernicus University, Torun, Poland.
Joanna
J
Lewandowska-Bieniek
Department of Plant Physiology and Biotechnology, Nicolaus Copernicus University, Torun, Poland.|Centre for Modern Interdisciplinary Technologies, Nicolaus Copernicus University, Torun, Poland.
Joanna
J
Szczepanek
Department of Pediatric Hematology and Oncology, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland.
Jan
J
Styczyński
Department of Plant Physiology and Biotechnology, Nicolaus Copernicus University, Torun, Poland.|Centre for Modern Interdisciplinary Technologies, Nicolaus Copernicus University, Torun, Poland.
Andrzej
A
Tretyn
D000970:Antineoplastic Agents / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002648:Child; D016000:Cluster Analysis; D055028:Comparative Genomic Hybridization; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D015973:Gene Expression Regulation, Leukemic; D023281:Genomics / Q000379:methods*; D006801:Humans; D015255:Idarubicin / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D008297:Male; D008942:Mitoxantrone / Q000494:pharmacology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology
D000970:Antineoplastic Agents; D008942:Mitoxantrone; D015255:Idarubicin
acute lymphoblastic leukemia; acute myeloblastic leukemia; comparative genomic hybridization; drug resistance; gene expression profiling