Signalling input from divergent pathways subverts B cell transformation

Lai N. Chan, Mark A. Murakami, Mark E. Robinson, Rebecca Caeser, Teresa Sadras, Jaewoong Lee, Kadriye Nehir Cosgun, Kohei Kume, Vishal Khairnar, Gang Xiao, Mohamed A. Ahmed, Eamon Aghania, Gauri Deb, Christian Hurtz, Seyedmehdi Shojaee, Chao Hong, Petri Pölönen, Matthew A. Nix, Zhengshan Chen, Chun Wei Chen, Jianjun Chen, Andreas Vogt, Merja Heinäniemi, Olli Lohi, Arun P. Wiita, Shai Izraeli, Huimin Geng, David M. Weinstock and Markus Müschen ()
Additional contact information
Lai N. Chan: City of Hope Comprehensive Cancer Center
Mark A. Murakami: Dana Farber Cancer Institute
Mark E. Robinson: City of Hope Comprehensive Cancer Center
Rebecca Caeser: University of California San Francisco
Teresa Sadras: City of Hope Comprehensive Cancer Center
Jaewoong Lee: City of Hope Comprehensive Cancer Center
Kadriye Nehir Cosgun: City of Hope Comprehensive Cancer Center
Kohei Kume: City of Hope Comprehensive Cancer Center
Vishal Khairnar: City of Hope Comprehensive Cancer Center
Gang Xiao: City of Hope Comprehensive Cancer Center
Mohamed A. Ahmed: City of Hope Comprehensive Cancer Center
Eamon Aghania: City of Hope Comprehensive Cancer Center
Gauri Deb: City of Hope Comprehensive Cancer Center
Christian Hurtz: University of California San Francisco
Seyedmehdi Shojaee: University of California San Francisco
Chao Hong: University of California San Francisco
Petri Pölönen: City of Hope Comprehensive Cancer Center
Matthew A. Nix: University of California San Francisco
Zhengshan Chen: City of Hope Comprehensive Cancer Center
Chun Wei Chen: City of Hope Comprehensive Cancer Center
Jianjun Chen: City of Hope Comprehensive Cancer Center
Andreas Vogt: University of Pittsburgh Drug Discovery Institute, Department of Computational and Systems Biology
Merja Heinäniemi: University of Eastern Finland
Olli Lohi: Tampere University Hospital and Tampere University, Faculty of Medicine and Health Technology
Arun P. Wiita: University of California San Francisco
Shai Izraeli: City of Hope Comprehensive Cancer Center
Huimin Geng: University of California San Francisco
David M. Weinstock: Dana Farber Cancer Institute
Markus Müschen: City of Hope Comprehensive Cancer Center

Nature, 2020, vol. 583, issue 7818, 845-851

Abstract: 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 expense of the principal oncogenic driver and reverses transformation. Conversely, deletion of divergent pathway components accelerates leukaemogenesis. Thus, persistence of divergent signalling pathways represents a powerful barrier to transformation, while convergence on one principal driver defines a central event in leukaemia initiation. Pharmacological reactivation of suppressed divergent circuits synergizes strongly with inhibition of the principal oncogenic driver. Hence, reactivation of divergent pathways can be leveraged as a previously unrecognized strategy to enhance treatment responses.

Date: 2020
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DOI: 10.1038/s41586-020-2513-4

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