4.7 Article

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

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NPJ PRECISION ONCOLOGY
卷 5, 期 1, 页码 -

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NATURE PORTFOLIO
DOI: 10.1038/s41698-021-00144-9

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  1. Associazione Italiana per la Ricerca sul Cancro (AIRC) [19818]
  2. AIRC 5 per 1000 project [21267]
  3. Italian Ministry of Health [RF-2016-02362930]
  4. Ministry of Education, University and Research [2017WXR7ZT_005]

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The study utilized single-cell analysis to reveal the increased genomic complexity during disease progression of myeloproliferative neoplasms and the immunomodulatory effects of the treatment drug. The results indicated that the mutation order of different genes was related to the disease evolution process, and Ruxolitinib might induce immunosuppressive effects, ultimately leading to AML transformation.
Disease progression of myeloproliferative neoplasms is the result of increased genomic complexity. Since the ability to predict disease evolution is crucial for clinical decisions, 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 the 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.

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