Tuning MPL Signaling to Influence Hematopoietic Stem Cell Differentiation and Inhibit Essential Thrombocythemia Progenitors

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2021 Jan 1

PMID 33384332

Citations 17

Authors

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

Gerlinde Wernig

Affiliations

Soon will be listed here.

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.

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