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

Blood. 2019 Jul 25;134(4):383-388. doi: 10.1182/blood.2018883140. Epub 2019 Jun 11.

Abstract

Activating mutations in FMS-like tyrosine kinase receptor-3 (FLT3) and Nucleophosmin-1 (NPM1) are most frequent alterations in acute myeloid leukemia (AML), and are often coincidental. The mutational status of NPM1 has strong prognostic relevance to patients with point mutations of the FLT3 tyrosine kinase domain (TKD), but the biological mechanism underlying this effect remains unclear. In the present study, we investigated the effect of the coincidence of NPM1c and FLT3-TKD. Although expression of FLT3-TKD is not sufficient to induce a disease in mice, coexpression with NPM1c rapidly leads to an aggressive myeloproliferative disease in mice with a latency of 31.5 days. Mechanistically, we could show that FLT3-TKD is able to activate the downstream effector molecule signal transducer and activator of transcription 5 (STAT5) exclusively in the presence of mutated NPM1c. Moreover, NPM1c alters the cellular localization of FLT3-TKD from the cell surface to the endoplasmic reticulum, which might thereby lead to the aberrant STAT5 activation. Importantly, aberrant STAT5 activation occurs not only in primary murine cells but also in patients with AML with combined FLT3-TKD and NPM1c mutations. Thus, our data indicate a new mechanism, how NPM1c mislocalizes FLT3-TKD and changes its signal transduction ability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Disease Models, Animal
  • Endoplasmic Reticulum / metabolism
  • Gene Duplication
  • Gene Expression Regulation, Leukemic
  • Humans
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / metabolism*
  • Mice
  • Mutation*
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Protein Transport
  • STAT5 Transcription Factor / metabolism
  • Signal Transduction*
  • Tandem Repeat Sequences
  • fms-Like Tyrosine Kinase 3 / genetics*
  • fms-Like Tyrosine Kinase 3 / metabolism*

Substances

  • Nuclear Proteins
  • STAT5 Transcription Factor
  • nucleophosmin
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3