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The molecular portrait of TCF3-PBX1 and TCF3-HLF acute lymphoblastic leukemia

Stanulla, Martin and Bourquin, Jean-Pierre (2015) The molecular portrait of TCF3-PBX1 and TCF3-HLF acute lymphoblastic leukemia. Nature Genetics.


TCF3-HLF fusion gene-positive acute lymphoblastic leukemia (ALL) is currently incurable.
Comparison of whole-genome, -exome and -transcriptome sequencing data from TCF3-HLFpositive
with treatment-susceptible TCF3-PBX1-positive ALL and thereof derived xenografts (PDX) revealed stable patterns of subgroup-associated mutations. In TCF3-HLF-positive ALL, recurrent mutually exclusive intragenic deletions of the lymphoid transcription factor gene PAX5
or somatic mutations in the non-translocated TCF3 allele – affecting upstream regulation of
PAX5 – in frequent conjunction with RAS pathway aberrations indicate the importance of a
characteristic mutational interaction. Despite a lymphoid-committed cell of origin in TCF3-HLF-
and TCF3-PBX1-positive ALL, TCF3-HLF-driven transcriptional signatures included elements consistent with reprogramming towards a hybrid hematopoietic state, as they were enriched for
stem, mesenchymal, and myeloid features. TCF3-HLF-positive ALL was associated with a distinct drug-activity profile including resistance to agents commonly used for its treatment.
Remarkable on-target sensitivity was observed for the BCL2-specific inhibitor ABT199,
underscoring the potential of our integrated model for exploring new treatment concepts for a
currently deadly disease.

Item Type: Article
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12