Affiliations 

  • 1 Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
  • 2 Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
  • 3 Department of Women's and Children's Health (SDB), Hematology-Oncology Laboratory, University of Padua, Padua, Italy
  • 4 The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
  • 5 National University Cancer Institute, Singapore, Singapore
  • 6 University of Malaya Medical Centre, University of Malaya, Kuala Lumpur, Malaysia
  • 7 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
  • 8 Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore. d.nizetic@qmul.ac.uk
Oncogene, 2021 01;40(4):746-762.
PMID: 33247204 DOI: 10.1038/s41388-020-01567-7

Abstract

Leukemias are routinely sub-typed for risk/outcome prediction and therapy choice using acquired mutations and chromosomal rearrangements. Down syndrome acute lymphoblastic leukemia (DS-ALL) is characterized by high frequency of CRLF2-rearrangements, JAK2-mutations, or RAS-pathway mutations. Intriguingly, JAK2 and RAS-mutations are mutually exclusive in leukemic sub-clones, causing dichotomy in therapeutic target choices. We prove in a cell model that elevated CRLF2 in combination with constitutionally active JAK2 is sufficient to activate wtRAS. On primary clinical DS-ALL samples, we show that wtRAS-activation is an obligatory consequence of mutated/hyperphosphorylated JAK2. We further prove that CRLF2-ligand TSLP boosts the direct binding of active PTPN11 to wtRAS, providing the molecular mechanism for the wtRAS activation. Pre-inhibition of RAS or PTPN11, but not of PI3K or JAK-signaling, prevented TSLP-induced RAS-GTP boost. Cytotoxicity assays on primary clinical DS-ALL samples demonstrated that, regardless of mutation status, high-risk leukemic cells could only be killed using RAS-inhibitor or PTPN11-inhibitor, but not PI3K/JAK-inhibitors, suggesting a unified treatment target for up to 80% of DS-ALL. Importantly, protein activities-based principal-component-analysis multivariate clusters analyzed for independent outcome prediction using Cox proportional-hazards model showed that protein-activity (but not mutation-status) was independently predictive of outcome, demanding a paradigm-shift in patient-stratification strategy for precision therapy in high-risk ALL.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.