Tuning MPL signaling to influence hematopoietic stem cell differentiation and inhibit essential thrombocythemia progenitors

Lu Cui, Ignacio Moraga, Tristan Lerbs, Camille Van Neste, Stephan Wilmes, Naotaka Tsutsumi, Aaron Claudius Trotman-Grant, Milica Gakovic, Sarah Andrews, Jason Gotlib, Spyros Darmanis, Martin Enge, Stephen Quake, Ian S. Hitchcock, Jacob Piehler, K. Christopher Garcia (Lead / Corresponding author), Gerlinde Wernig (Lead / Corresponding author)

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Abstract

Thrombopoietin (TPO) and the TPO-receptor (TPO-R, or c-MPL) are essential for hematopoietic stem cell (HSC) maintenance and megakaryocyte differentiation. Agents that can modulate TPO-R signaling are highly desirable for both basic research and clinical utility. We developed a series of surrogate protein ligands for TPO-R, in the form of diabodies (DBs), that homodimerize TPO-R on the cell surface in geometries that are dictated by the DB receptor binding epitope, in effect "tuning" downstream signaling responses. These surrogate ligands exhibit diverse pharmacological properties, inducing graded signaling outputs, from full to partial TPO agonism, thus decoupling the dual functions of TPO/TPO-R. Using single-cell RNA sequencing and HSC self-renewal assays we find that partial agonistic diabodies preserved the stem-like properties of cultured HSCs, but also blocked oncogenic colony formation in essential thrombocythemia (ET) through inverse agonism. Our data suggest that dampening downstream TPO signaling is a powerful approach not only for HSC preservation in culture, but also for inhibiting oncogenic signaling through the TPO-R.

Original languageEnglish
Article numbere2017849118
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number2
Early online date31 Dec 2020
DOIs
Publication statusPublished - 12 Jan 2021

Keywords

  • Hematopoietic stem cells
  • Megakaryopoiesis
  • Myeloproliferative neoplasm
  • Thrombopoietin signaling

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