TY - JOUR
T1 - STAT3 mediates oncogenic addiction to TEL-AML1 in t(12;21) acute lymphoblastic leukemia
AU - Mangolini, Maurizio
AU - de Boer, Jasper
AU - Walf-Vorderwülbecke, Vanessa
AU - Pieters, Rob
AU - den Boer, Monique L
AU - Williams, Owen
N1 - Publisher Copyright:
© 2013 by The American Society of Hematology.
PY - 2013/7/25
Y1 - 2013/7/25
N2 - The t(12;21)(p13;q22) translocation is the most common chromosomal abnormality in pediatric leukemia. Although this rearrangement involves 2 well-characterized transcription factors, TEL and AML1, the molecular pathways affected by the result of the translocation remain largely unknown. Also in light of recent studies showing genetic and functional heterogeneities in cells responsible for cancer clone maintenance and propagation, targeting a single common deregulated pathway may be critical for the success of novel therapies. Here we describe a novel signaling pathway that is essential for oncogenic addiction in TEL-AML1 leukemia. Our data indicate a direct role for TEL-AML1, via increasing the activity of RAC1, in regulating the phosphorylation of signal transducer and activator of transcription 3 (STAT3), which results in transcriptional induction of MYC. We demonstrate that human leukemic cell lines carrying this translocation are highly sensitive to treatment with S3I-201, a specific STAT3 inhibitor, and, more interestingly, that primary human leukemic samples are also responsive to the drug in the same concentration range. Thus, STAT3 inhibition represents a promising possible therapeutic strategy for the treatment of TEL-AML1 leukemia.
AB - The t(12;21)(p13;q22) translocation is the most common chromosomal abnormality in pediatric leukemia. Although this rearrangement involves 2 well-characterized transcription factors, TEL and AML1, the molecular pathways affected by the result of the translocation remain largely unknown. Also in light of recent studies showing genetic and functional heterogeneities in cells responsible for cancer clone maintenance and propagation, targeting a single common deregulated pathway may be critical for the success of novel therapies. Here we describe a novel signaling pathway that is essential for oncogenic addiction in TEL-AML1 leukemia. Our data indicate a direct role for TEL-AML1, via increasing the activity of RAC1, in regulating the phosphorylation of signal transducer and activator of transcription 3 (STAT3), which results in transcriptional induction of MYC. We demonstrate that human leukemic cell lines carrying this translocation are highly sensitive to treatment with S3I-201, a specific STAT3 inhibitor, and, more interestingly, that primary human leukemic samples are also responsive to the drug in the same concentration range. Thus, STAT3 inhibition represents a promising possible therapeutic strategy for the treatment of TEL-AML1 leukemia.
KW - Animals
KW - Apoptosis/genetics
KW - Cell Proliferation
KW - Cell Transformation, Neoplastic/genetics
KW - Cells, Cultured
KW - Chromosomes, Human, Pair 12/genetics
KW - Chromosomes, Human, Pair 21/genetics
KW - Core Binding Factor Alpha 2 Subunit/genetics
KW - Humans
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Transgenic
KW - Oncogene Proteins, Fusion/genetics
KW - Oncogenes/genetics
KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics
KW - STAT3 Transcription Factor/genetics
KW - Translocation, Genetic/physiology
UR - http://www.scopus.com/inward/record.url?scp=84886895426&partnerID=8YFLogxK
U2 - 10.1182/blood-2012-11-465252
DO - 10.1182/blood-2012-11-465252
M3 - Article
C2 - 23741012
SN - 0006-4971
VL - 122
SP - 542
EP - 549
JO - Blood
JF - Blood
IS - 4
ER -