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NPM1c alters FLT3-D835Y localization and signaling in acute myeloid leukemia

Alina Rudorf1,2,3, Tony Andreas Müller1, Cathrin Klingeberg1

  • 1Department of Hematology and Oncology, Freiburg University Medical Center, Albert-Ludwigs-University of Freiburg, Freiburg, Germany.

Blood
|June 13, 2019
PubMed

Insights

Co-occurring mutations in FMS-like tyrosine kinase receptor-3 (FLT3) and Nucleophosmin-1 (NPM1) in acute myeloid leukemia (AML) accelerate disease. Mutated NPM1 causes FLT3 to activate STAT5, leading to aggressive myeloproliferative disease.

Area of Science:

  • Hematology
  • Molecular Biology
  • Cancer Research

Background:

  • Activating mutations in FMS-like tyrosine kinase receptor-3 (FLT3) and Nucleophosmin-1 (NPM1) are common in acute myeloid leukemia (AML).
  • The prognostic significance of NPM1 mutations in patients with FLT3 tyrosine kinase domain (TKD) mutations is known, but the underlying biological mechanism is unclear.

Purpose of the Study:

  • To investigate the mechanistic effect of the coincidence of NPM1c and FLT3-TKD mutations in AML.
  • To elucidate how NPM1c influences FLT3-TKD signaling and disease progression.

Main Methods:

  • Investigated the coexpression of FLT3-TKD and NPM1c in murine models.
  • Analyzed downstream signaling pathways, including signal transducer and activator of transcription 5 (STAT5) activation.
  • Examined the cellular localization of FLT3-TKD in the presence of NPM1c.

Main Results:

  • Coexpression of FLT3-TKD and NPM1c in mice rapidly induced aggressive myeloproliferative disease with a short latency (31.5 days).
  • FLT3-TKD activated STAT5 exclusively in the presence of mutated NPM1c.
  • NPM1c altered FLT3-TKD localization from the cell surface to the endoplasmic reticulum, potentially causing aberrant STAT5 activation.
  • Aberrant STAT5 activation was observed in both murine cells and human AML patients with combined FLT3-TKD and NPM1c mutations.

Conclusions:

  • NPM1c mislocalizes FLT3-TKD to the endoplasmic reticulum.
  • This mislocalization alters FLT3-TKD's signal transduction ability, leading to aberrant STAT5 activation.
  • The findings reveal a novel mechanism contributing to aggressive AML pathogenesis driven by combined FLT3-TKD and NPM1c mutations.

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