Sos1 deficiency ameliorates oncogenic KRAS-mediated hematopoietic stem cell exhaustion and myeloid progenitor expansion

Abstract

Constitutive KRAS activating mutations are prevalent in hematopoietic malignancies. Our previous study showed that the deficiency of Sos1 prolongs the survival of Kras^G12D/+ mice. However, whether Sos1 deletion ameliorates oncogenic Kras-mediated hematopoietic defects remains unknown. Here, we found that Sos1 deletion restored Kras^G12D-mediated hematopoietic stem cell (HSC) and multipotent progenitor (MPP) exhaustion by maintaining quiescent HSC and MPP pools. Sos1 knockout attenuates hyperactivation of ERK signaling in Kras^G12D/+ HSCs and MPPs. Additionally, the loss of Sos1 reduced the frequency and colony-forming capability of myeloid progenitors in Kras^G12D/+ mice, resulting in a less severe myeloproliferative neoplasm phenotype. Moreover, Sos1 knockout prolonged the survival of Kras^G12D/+ mice in a cell-autonomous manner. In general, cells with Sos1 deletion remained sensitive to MEK and JAK inhibition, suggesting that combined Sos1 inhibition and other therapies could be a promising strategy for the treatment of oncogenic KRAS-driven leukemia.

Keywords

Sos1 / Kras / Hematopoietic stem cell / Quiescent / ERK signaling

Availability of data and material

The data generated or analyzed in this study have been included in a published article. These data will be available upon request.

Ethical approval of studies and informed consent

All animal experiments were conducted in accordance with the National Research Council's Guide for the Care and Use of Laboratory Animals and were approved by the Animal Care and Use Committee at UW-Madison.) The study was approved by the Association for the Assessment and Accreditation of Laboratory Animal Care (approval no. M005328).

Funding

This work was supported by the National Nature Science Foundation of China (81673644), the Research Projects of Guangdong Provincial Bureau of Traditional Chinese Medicine (20181261), and the Science and Technology Plan (Medical and Health) Project of Huizhou (2018Y158).

CRediT authorship contribution statement

Maoshuo Yang: Writing - review & editing, Writing - original draft, Formal analysis, Data curation, Conceptualization. Lanlan Liu: Formal analysis, Data curation, Conceptualization. Yaqing Miao: Formal analysis. Yongxin Jia: Validation. Sijia Tian: Formal analysis. Limei Wang: Validation. Fabao Liu: Writing - review & editing, Validation, Supervision. Xiaona You: Writing - review & editing, Writing - original draft, Validation, Supervision, Funding acquisition, Formal analysis, Data curation, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

We thank the University of Wisconsin Carbone Comprehensive Cancer Center for the use of Shared Services (Flow Cytometry Laboratory and Animal Models Shared Resource) to complete this research.

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