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

doi:10.1016/j.pathol.2022.05.015

Novel modes of MPL activation in triple-negative myeloproliferative neoplasms

Pathology. 2023 Feb;55(1):77-85. doi: 10.1016/j.pathol.2022.05.015. Epub 2022 Aug 5.

Authors

Saumya E Samaraweera¹, Tatjana Geukens², Debora A Casolari¹, Tran Nguyen¹, Caitlyn Sun³, Sheree Bailey⁴, Sarah Moore⁵, Jinghua Feng⁶, Andreas W Schreiber⁷, Wendy T Parker⁵, Anna L Brown⁸, Carolyn Butcher⁹, Peter G Bardy⁹, Michael Osborn¹⁰, Hamish S Scott¹¹, Dipti Talaulikar¹², Carolyn S Grove¹³, Christopher N Hahn¹⁴, Richard J D'Andrea¹, David M Ross¹⁵

Affiliations

¹ Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia.
² Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia; Department of Oncology, KU Leuven, Leuven, Belgium.
³ Department of Haematology, Royal Adelaide Hospital, Adelaide, SA, Australia; Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.
⁴ UniSA Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia; Health and Biomedical Innovation, Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia.
⁵ Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia.
⁶ Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia; ACRF Cancer Genomics Facility, SA Pathology, Adelaide, SA, Australia.
⁷ Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia; UniSA Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia; ACRF Cancer Genomics Facility, SA Pathology, Adelaide, SA, Australia; School of Biological Sciences, The University of Adelaide, Adelaide, SA, Australia.
⁸ Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia; Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia; Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia.
⁹ Department of Haematology, Royal Adelaide Hospital, Adelaide, SA, Australia.
¹⁰ South Australia/Northern Territory Youth Cancer Service, Royal Adelaide Hospital, Adelaide, SA, Australia; Department of Haematology and Oncology, Women's and Children's Hospital, North Adelaide, SA, Australia.
¹¹ Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia; Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia; UniSA Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia; Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia; ACRF Cancer Genomics Facility, SA Pathology, Adelaide, SA, Australia.
¹² Haematology Translational Research Unit, ACT Pathology, Canberra Hospital, Canberra, ACT, Australia.
¹³ Department of Haematology, Sir Charles Gairdner Hospital and PathWest, Perth, WA, Australia.
¹⁴ Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia; Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia; UniSA Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia; Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia.
¹⁵ Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia; Department of Haematology, Royal Adelaide Hospital, Adelaide, SA, Australia; Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia; Department of Haematology and Genetic Pathology, Flinders University and Medical Centre, Bedford Park, SA, Australia. Electronic address: [email protected].

PMID: 36031433
DOI: 10.1016/j.pathol.2022.05.015

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.

Keywords: MPL activation; MPL variants; Myeloproliferative neoplasms; triple-negative MPN.

MeSH terms

Calreticulin / genetics
Calreticulin / metabolism
Humans
Mutation
Myeloproliferative Disorders* / diagnosis
Myeloproliferative Disorders* / genetics
Neoplasms*
Receptors, Thrombopoietin / genetics

Substances

Receptors, Thrombopoietin
Calreticulin
MPL protein, human