Signalling input from divergent pathways subverts B cell transformation.

Nature
Lai N. ChanMarkus Müschen

Abstract

Malignant transformation of cells typically involves several genetic lesions, whose combined activity gives rise to cancer1. Here we analyse 1,148 patient-derived B-cell leukaemia (B-ALL) samples, and find that individual mutations do not promote leukaemogenesis unless they converge on one single oncogenic pathway that is characteristic of the differentiation stage of transformed B cells. Mutations that are not aligned with this central oncogenic driver activate divergent pathways and subvert transformation. Oncogenic lesions in B-ALL frequently mimic signalling through cytokine receptors at the pro-B-cell stage (via activation of the signal-transduction protein STAT5)2-4 or pre-B-cell receptors in more mature cells (via activation of the protein kinase ERK)5-8. STAT5- and ERK-activating lesions are found frequently, but occur together in only around 3% of cases (P = 2.2 × 10-16). Single-cell mutation and phospho-protein analyses reveal the segregation of oncogenic STAT5 and ERK activation to competing clones. STAT5 and ERK engage opposing biochemical and transcriptional programs that are orchestrated by the transcription factors MYC and BCL6, respectively. Genetic reactivation of the divergent (suppressed) pathway comes at the...Continue Reading

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Citations

Apr 9, 2021·Science Translational Medicine·Julia P VainonenJukka Westermarck
May 7, 2021·Molecular Oncology·Matheus Henrique Dias, René Bernards
Jul 25, 2021·International Journal of Molecular Sciences·Klaus FortscheggerSabine Strehl
Jun 29, 2021·Arthritis & Rheumatology·Christine LiuJohn J O'Shea

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Methods Mentioned

BETA
xenografts
amplicon sequencing
biopsy
xenograft
chips
chip
flow cytometry
immunoprecipitation

Software Mentioned

ProteinSimple
Scout
GraphPad Prism
R package
MACS
igraph
ImageJ
R
Hmisc
R package ‘ survival ’

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