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

• Published in: Cells (Basel, Switzerland) Vol. 12; no. 13; p. 1798
• Main Authors: Ehm, Patrick, Rietow, Ruth, Wegner, Wiebke, Bußmann, Lara, Kriegs, Malte, Dierck, Kevin, Horn, Stefan, Streichert, Thomas, Horstmann, Martin, Jücker, Manfred
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.07.2023; MDPI
• Subjects: 1-Phosphatidylinositol 3-kinase; Acute lymphoblastic leukemia; Acute lymphocytic leukemia; AKT protein; Animals; Antibodies; Cancer; Care and treatment; Cell proliferation; Cell signaling; Cells; Cloning; Demographic aspects; Diagnosis; Down-regulation; Gene expression; Humans; Inositol; Inositol-1,4,5-trisphosphate 5-phosphatase; Kinases; Leukemia; Lymphocytes T; Medical prognosis; Mice; Mice, Inbred Strains; Mutation; myo-Inositol-1 (or 4)-monophosphatase; NTRK; Patient outcomes; Patients; PDGFR; Penicillin; Phosphatase; Phosphatidylinositol 3-Kinases - metabolism; PI3K/AKT/mTOR-signaling pathway; Plasmids; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Protein-tyrosine kinase receptors; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Relapse; SHIP1; Signal transduction; T-ALL; Therapeutic targets; Threonine; Transplantation; Transplantation, Heterologous; Tumor suppressor genes; Tumors; Xenotransplantation; Germany; PDGFR; PI3K/AKT/mTOR-signaling pathway; NTRK; T-ALL; SHIP1
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells12131798

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.