Klin Padiatr 2017; 229(03): 182-195
DOI: 10.1055/s-0037-1602217
Top 5 Cell biology and mechanisms of disease
Georg Thieme Verlag KG Stuttgart · New York

Illuminating the leukemogenic transformation activity of TCF3-HLF in pediatric ALL

B Mouttet
1   University Children's Hospital, Zurich, Switzerland
,
Y Huang
1   University Children's Hospital, Zurich, Switzerland
,
HJ Warnatz
2   Max Planck Institute for Molecular Genetics, Berlin, Germany
,
ML Yaspo
2   Max Planck Institute for Molecular Genetics, Berlin, Germany
,
B Bornhauser
1   University Children's Hospital, Zurich, Switzerland
,
JP Bourquin
1   University Children's Hospital, Zurich, Switzerland
› Author Affiliations
Further Information

Publication History

Publication Date:
30 May 2017 (online)

Also available at
 

Introduction:

Resistant disease remains a major problem in paediatric oncology. The translocation t(17;19) defines an ALL subgroup with dismal outcome and no effective treatment options.

Methods:

To decipher the composition of the TCF3-HLF complex and the landscape of both the affected gene regulatory elements as well as its epigenetic landscape, we used a combined proteomic (mass spectrometry) and genomic (ChIP-Seq) approach. We further investigated TCF3-HLF by functional genomics as well as by pharmacological interference.

Results:

We identified cofactors including transcription factors such as ETS factors important for B-cell development and EP300, a key epigenetic regulator. ChIP-Seq showed a strong enrichment of TCF3-HLF at ETS binding motifs on superenhancer sites. Moreover, functional interference showed a strong dependency of the leukemia on ETS factors as well as EP300. Pharmacological inhibition of EP300 showed synergistic effect when combined with conventional chemotherapeutic agents.

Conclusion:

Our data indicate that TCF3-HLF drives ALL through deregulation of distinct B-cell transcription factors and epigenetic regulators.