Mutated clones driving leukemic transformation are already detectable at the single cell level in CD34-positive cells in the chronic phase of primary myelofibrosis

ABSTRACT Disease progression of myeloproliferative neoplasms is the result of increased genomic complexity. Since the ability to predict disease evolution is crucial for clinical decision, we studied single cell genomics and transcriptomics of CD34-positive cells from a primary myelofibrosis (PMF) p...

Full description

Saved in:
Bibliographic Details
Published inbioRxiv
Main Authors Parenti, Sandra, Rontauroli, Sebastiano, Carretta, Chiara, Mallia, Selene, Genovese, Elena, Chiereghin, Chiara, Peano, Clelia, Tavernari, Lara, Bianchi, Elisa, Fantini, Sebastian, Sartini, Stefano, Romano, Oriana, Bicciato, Silvio, Tagliafico, Enrico, Matteo Della Porta, Manfredini, Rossella
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 07.12.2020
Subjects
Acute myeloid leukemia
CD34 antigen
Cloning
Genetic transformation
Genomics
Immunosuppression
Interferon
Myelofibrosis
Myeloid leukemia
p53 Protein
Online AccessGet full text

Cover

More Information
Summary:ABSTRACT Disease progression of myeloproliferative neoplasms is the result of increased genomic complexity. Since the ability to predict disease evolution is crucial for clinical decision, we studied single cell genomics and transcriptomics of CD34-positive cells from a primary myelofibrosis (PMF) patient who progressed to acute myeloid Leukemia (AML) while receiving Ruxolitinib. Single cell genomics allowed the reconstruction of clonal hierarchy and demonstrated that TET2 was the first mutated gene while FLT3 was the last one. Disease evolution was accompanied by increased clonal heterogeneity and mutational rate, but clones carrying TP53 and FLT3 mutations were already present in chronic phase. Single cell transcriptomics unraveled repression of interferon signaling suggesting an immunosuppressive effect exerted by Ruxolitinib. Moreover, AML transformation was associated with a differentiative block and immune escape. These results suggest that single cell analysis can unmask tumor heterogeneity and provide meaningful insights about PMF progression that might guide personalized therapy. Competing Interest Statement The authors have declared no competing interest. Footnotes * https://identifiers.org/geo:GSE153319
DOI:10.1101/2020.12.07.414177