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

Alina Rudorf, Tony Andreas Müller, Cathrin Klingeberg, Stefanie Kreutmair, Teresa Poggio, Sivahari Prasad Gorantla, Tamina Rückert, Annette Schmitt-Graeff, Anina Gengenbacher, Peter Paschka, Claudia Baldus, Robert Zeiser, George S. Vassiliou, Allan Bradley, Justus Duyster and Anna Lena Illert

Key Points

  • Two common AML mutations, NPM1c and FLT3-TKD, cooperate to induce a rapid onset disease in mice.

  • Mechanistically, NPM1c alters FLT3-TKD localization and changes its signaling properties, which may be useful for therapeutic intervention.

Abstract

Activating mutations in FLT3 and NPM1 are most frequent alterations in acute myeloid leukemia (AML) and 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 impact of the coincidence of NPM1c and FLT3-TKD. While expression of FLT3-TKD is not sufficient to induce a disease in mice, co-expression 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 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 not only occurs in primary murine cells but also in AML patients 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.

  • Submitted October 30, 2018.
  • Revision received June 11, 2019.
  • Accepted April 19, 2019.