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FLI1 is associated with regulation of DNA methylation and megakaryocytic differentiation in FPDMM caused by a RUNX1

Yuki Tanaka1, Yuri Nakanishi1, Erina Furuhata1

  • 1Laboratory for Cellular Function Conversion Technology, RIKEN Center for Integrative Medical Sciences (IMS), RIKEN Yokohama Campus, 1-7-22 Suehiro-Cho, Tsurumi-Ku, Yokohama City, Kanagawa, 230-0045, Japan.

Scientific Reports
|June 18, 2024
PubMed

Insights

Familial platelet disorder with associated myeloid malignancies (FPDMM) involves RUNX1 mutations affecting blood cell development. This study reveals FLI1

Area of Science:

  • Hematology
  • Genetics
  • Epigenetics

Background:

  • Familial platelet disorder with associated myeloid malignancies (FPDMM) is an inherited condition linked to RUNX1 mutations.
  • FPDMM patients exhibit low platelet counts, impaired platelet function, and increased risk of blood cancers.
  • The DNA methylation status in FPDMM is largely unknown due to limited research models.

Purpose of the Study:

  • To investigate the DNA methylation patterns in FPDMM using patient-derived cellular models.
  • To explore the role of RUNX1 mutations and their impact on hematopoietic differentiation and DNA methylation.
  • To identify potential therapeutic targets for FPDMM.

Main Methods:

  • Generated human induced pluripotent stem cells (iPSCs) with RUNX1 mutations mimicking FPDMM.
  • Analyzed hematopoietic progenitor cell (HPC) and megakaryocyte (Mk) differentiation from these iPSCs.
  • Performed genome-wide DNA methylation analysis and transcription factor motif enrichment analysis.
  • Assessed the role of FLI1 in DNA methylation and megakaryopoiesis.

Main Results:

  • FPDMM-mimicking iPSCs showed impaired HPC and Mk differentiation.
  • Distinct DNA methylation patterns were observed in FPDMM-mimicking HPCs, with hypermethylation enriched for ETS TF motifs.
  • RUNX1 mutations, particularly in the transactivation domain (TAD), led to decreased FLI1 expression.
  • FLI1 overexpression corrected megakaryocytic differentiation defects and normalized DNA methylation.

Conclusions:

  • FLI1 plays a critical role in regulating DNA methylation and megakaryocytic differentiation in FPDMM.
  • Restoring FLI1 function may be a therapeutic strategy for FPDMM with RUNX1 TAD mutations.
  • This study provides novel insights into the epigenetic mechanisms underlying FPDMM.
Keywords:
FLI1DNA demethylationDNA methylation analysisFamilial platelet disorder with associated myeloid malignanciesMegakaryocytic differentiation

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