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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.

  • Ehm, Patrick1, 2
  • Rietow, Ruth1, 2
  • Wegner, Wiebke1
  • Bußmann, Lara3, 4
  • Kriegs, Malte4, 5
  • Dierck, Kevin2
  • Horn, Stefan6
  • Streichert, Thomas7
  • Horstmann, Martin2
  • Jücker, Manfred1
  • 1 Institute of Biochemistry and Signal Transduction, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany. , (Germany)
  • 2 Research Institute Children's Cancer Center Hamburg, Hamburg and Department of Pediatric Oncology and Hematology, University Medical Center, 20246 Hamburg, Germany. , (Germany)
  • 3 Department of Otorhinolaryngology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. , (Germany)
  • 4 UCCH Kinomics Core Facility, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. , (Germany)
  • 5 Center for Oncology, Clinic for Radiation Therapy and Radiation Oncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. , (Germany)
  • 6 Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. , (Germany)
  • 7 Institute for Clinical Chemistry, University Hospital Köln, 50937 Cologne, Germany. , (Germany)
Published Article
Publication Date
Jul 06, 2023
DOI: 10.3390/cells12131798
PMID: 37443832


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.

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