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


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.

SUBMITTER: Cui L 

PROVIDER: S-EPMC7812794 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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

Cui Lu L   Moraga Ignacio I   Lerbs Tristan T   Van Neste Camille C   Wilmes Stephan S   Tsutsumi Naotaka N   Trotman-Grant Aaron Claudius AC   Gakovic Milica M   Andrews Sarah S   Gotlib Jason J   Darmanis Spyros S   Enge Martin M   Quake Stephen S   Hitchcock Ian S IS   Piehler Jacob J   Garcia K Christopher KC   Wernig Gerlinde G  

Proceedings of the National Academy of Sciences of the United States of America 20210101 2


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 s  ...[more]

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