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Leuk Lymphoma. 2011 Feb;52 Suppl 1:30-44. doi: 10.3109/10428194.2010.546914. Epub 2011 Jan 11.

BCR-ABL1 kinase-dependent alteration of mRNA metabolism: potential alternatives for therapeutic intervention.

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1
Human Cancer Genetics Program, Depatment of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center and Center for RNA Biology, The Ohio State University, Columbus, OH 43210-2207, USA. danilo.perrotti@osumc.edu

Abstract

The use of first- and second-generation tyrosine kinase inhibitors (TKIs) significantly improves prognosis for patients with early chronic phase chronic myeloid leukemia (CML) and efficiently counteracts leukemia in most patients with CML bearing a disease characterized by the expression of BCR-ABL1 mutants. However, the so-called 'tinib' TKIs (e.g. imatinib, nilotinib, dasatinib, and bosutinib) are both ineffective in patients who undergo blastic transformation and unable to eradicate CML at the stem cell level. This raises a few important questions. Is BCR-ABL1 expression and/or activity essential for blastic transformation? Is blastic transformation the result of genetic or epigenetic events that occur at the stem cell level which only become apparent in the granulocyte-macrophage progenitor (GMP) cell pool, or does it arise directly at the GMP level? As altered mRNA metabolism contributes to the phenotype of blast crisis CML progenitors (decreased translation of tumor suppressor genes and transcription factors essential for terminal differentiation and increased translation of anti-apoptotic genes), one attractive concept is to restore levels of these essential molecules to their normal levels. In this review, we discuss the mechanisms by which mRNA processing, translation, and degradation are deregulated in BCR-ABL1 myeloid blast crisis CML progenitors, and present encouraging results from studies with pharmacologic inhibitors which support their inclusion in the clinic.

PMID:
21299458
DOI:
10.3109/10428194.2010.546914
[Indexed for MEDLINE]
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