SHIP1 Is Present but Strongly Downregulated in T-ALL, and after Restoration Suppresses Leukemia Growth in a T-ALL Xenotransplantation Mouse Model

Ehm, Patrick; Rietow, Ruth; Wegner, Wiebke; Bußmann, Lara; Kriegs, Malte; Dierck, Kevin; Horn, Stefan; Streichert, Thomas; Horstmann, Martin; Jücker, Manfred

doi:10.3390/cells12131798

Open AccessArticle

SHIP1 Is Present but Strongly Downregulated in T-ALL, and after Restoration Suppresses Leukemia Growth in a T-ALL Xenotransplantation Mouse Model

by

Patrick Ehm

^1,2,*,

Ruth Rietow

^1,2,

Wiebke Wegner

¹,

Lara Bußmann

^3,4,

Malte Kriegs

^4,5,

Kevin Dierck

²,

Stefan Horn

⁶,

Thomas Streichert

⁷

,

Martin Horstmann

² and

Manfred Jücker

¹

Institute of Biochemistry and Signal Transduction, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany

²

Research Institute Children’s Cancer Center Hamburg, Hamburg and Department of Pediatric Oncology and Hematology, University Medical Center, 20246 Hamburg, Germany

³

Department of Otorhinolaryngology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany

⁴

UCCH Kinomics Core Facility, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany

⁵

Center for Oncology, Clinic for Radiation Therapy and Radiation Oncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany

⁶

Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany

⁷

Institute for Clinical Chemistry, University Hospital Köln, 50937 Cologne, Germany

^*

Author to whom correspondence should be addressed.

Cells 2023, 12(13), 1798; https://doi.org/10.3390/cells12131798

Submission received: 25 May 2023 / Revised: 23 June 2023 / Accepted: 3 July 2023 / Published: 6 July 2023

(This article belongs to the Section Cell Signaling)

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Abstract

Acute lymphoblastic leukemia (ALL) is the most common cause of cancer-related death in children. Despite significantly increased chances of cure, especially for high-risk ALL patients, it still represents a poor prognosis for a substantial fraction of patients. Misregulated proteins in central switching points of the cellular signaling pathways represent potentially important therapeutic targets. Recently, the inositol phosphatase SHIP1 (SH2-containing inositol 5-phosphatase) has been considered as a tumor suppressor in leukemia. SHIP1 serves as an important negative regulator of the PI3K/AKT signaling pathway, which is frequently constitutively activated in primary T-ALL. In contrast to other reports, we show for the first time that SHIP1 has not been lost in T-ALL cells, but is strongly downregulated. Reduced expression of SHIP1 leads to an increased activation of the PI3K/AKT signaling pathway. SHIP1-mRNA expression is frequently reduced in primary T-ALL samples, which is recapitulated by the decrease in SHIP1 expression at the protein level in seven out of eight available T-ALL patient samples. In addition, we investigated the change in the activity profile of tyrosine and serine/threonine kinases after the restoration of SHIP1 expression in Jurkat T-ALL cells. The tyrosine kinase receptor subfamilies of NTRK and PDGFR, which are upregulated in T-ALL subgroups with low SHIP1 expression, are significantly disabled after SHIP1 reconstitution. Lentiviral-mediated reconstitution of SHIP1 expression in Jurkat cells points to a decreased cellular proliferation upon transplantation into NSG mice in comparison to the control cohort. Together, our findings will help to elucidate the complex network of cell signaling proteins, further support a functional role for SHIP1 as tumor suppressor in T-ALL and, much more importantly, show that full-length SHIP1 is expressed in T-ALL samples.

Keywords: SHIP1; T-ALL; PI3K/AKT/mTOR-signaling pathway; NTRK; PDGFR

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MDPI and ACS Style

Ehm, P.; Rietow, R.; Wegner, W.; Bußmann, L.; Kriegs, M.; Dierck, K.; Horn, S.; Streichert, T.; Horstmann, M.; Jücker, M. SHIP1 Is Present but Strongly Downregulated in T-ALL, and after Restoration Suppresses Leukemia Growth in a T-ALL Xenotransplantation Mouse Model. Cells 2023, 12, 1798. https://doi.org/10.3390/cells12131798

AMA Style

Ehm P, Rietow R, Wegner W, Bußmann L, Kriegs M, Dierck K, Horn S, Streichert T, Horstmann M, Jücker M. SHIP1 Is Present but Strongly Downregulated in T-ALL, and after Restoration Suppresses Leukemia Growth in a T-ALL Xenotransplantation Mouse Model. Cells. 2023; 12(13):1798. https://doi.org/10.3390/cells12131798

Chicago/Turabian Style

Ehm, Patrick, Ruth Rietow, Wiebke Wegner, Lara Bußmann, Malte Kriegs, Kevin Dierck, Stefan Horn, Thomas Streichert, Martin Horstmann, and Manfred Jücker. 2023. "SHIP1 Is Present but Strongly Downregulated in T-ALL, and after Restoration Suppresses Leukemia Growth in a T-ALL Xenotransplantation Mouse Model" Cells 12, no. 13: 1798. https://doi.org/10.3390/cells12131798

APA Style

Ehm, P., Rietow, R., Wegner, W., Bußmann, L., Kriegs, M., Dierck, K., Horn, S., Streichert, T., Horstmann, M., & Jücker, M. (2023). SHIP1 Is Present but Strongly Downregulated in T-ALL, and after Restoration Suppresses Leukemia Growth in a T-ALL Xenotransplantation Mouse Model. Cells, 12(13), 1798. https://doi.org/10.3390/cells12131798

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SHIP1 Is Present but Strongly Downregulated in T-ALL, and after Restoration Suppresses Leukemia Growth in a T-ALL Xenotransplantation Mouse Model

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