Novel modes of MPL activation in triple-negative myeloproliferative neoplasms

Saumya E. Samaraweera, Tatjana Geukens, Debora A. Casolari, Tran Nguyen, Caitlyn Sun, Sheree Bailey, Sarah Moore, Jinghua Feng, Andreas W. Schreiber, Wendy T. Parker, Anna L. Brown, Carolyn Butcher, Peter G. Bardy, Michael Osborn, Hamish S. Scott, Dipti Talaulikar, Carolyn S. Grove, Christopher N. Hahn, Richard J. D'Andrea, David M. Ross

Research output: Contribution to journalArticlepeer-review

Abstract

The identification of a somatic mutation associated with myeloid malignancy is of diagnostic importance in myeloproliferative neoplasms (MPNs). Individuals with no mutation detected in common screening tests for variants in JAK2, CALR, and MPL are described as ‘triple-negative’ and pose a diagnostic challenge if there is no other evidence of a clonal disorder. To identify potential drivers that might explain the clinical phenotype, we used an extended sequencing panel to characterise a cohort of 44 previously diagnosed triple-negative MPN patients for canonical mutations in JAK2, MPL and CALR at low variant allele frequency (found in 4/44 patients), less common variants in the JAK-STAT signalling pathway (12 patients), or other variants in recurrently mutated genes from myeloid malignancies (18 patients), including hotspot variants of potential clinical relevance in eight patients. In one patient with thrombocytosis we identified biallelic germline MPL variants. Neither MPL variant was activating in cell proliferation assays, and one of the variants was not expressed on the cell surface, yet co-expression of both variants led to thrombopoietin hypersensitivity. Our results highlight the clinical value of extended sequencing including germline variant analysis and illustrate the need for detailed functional assays to determine whether rare variants in JAK2 or MPL are pathogenic.

Original languageEnglish
Pages (from-to)77-85
Number of pages9
JournalPathology
Volume55
Issue number1
DOIs
Publication statusPublished or Issued - Feb 2023
Externally publishedYes

Keywords

  • MPL activation
  • MPL variants
  • Myeloproliferative neoplasms
  • triple-negative MPN

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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