SHIP1, but not an AML-derived SHIP1 mutant, suppresses myeloid leukemia growth in a xenotransplantation mouse model

Abstract

Constitutive activation of the PI3K/AKT signaling pathway is found in ~50-70% of AML patients. The SH2-containing inositol 5-phosphatase 1 (SHIP1) is a negative regulator of PI3K/AKT signaling in hematopoietic cells. SHIP1 knockout mice develop a myeloproliferative syndrome and concomitant deletion of SHIP1 and the tumor suppressor PTEN leads to the development of lethal B-cell lymphomas. In the study presented here, we investigated the role of SHIP1 as a tumor suppressor in myeloid leukemia cells in an in vivo xenograft transplantation model. NSG Mice transplanted with UKE-1 cells derived from a secondary AML showed a significantly extended lifespan after lentiviral-mediated overexpression of SHIP1 in comparison to the vector control cohort. In contrast, the AML-derived SHIP1 mutant, which has a strongly reduced enzymatic activity showed a significant reversion of the SHIP1-induced prolongation of the survival time. In addition, the analysis of 290 AML patients revealed a correlation between expression of SHIP1 and overall survival of the AML patients. These results indicate that SHIP1 can act as a tumor suppressor in acute myeloid leukemia cells and that higher SHIP1 expression is associated with prolonged overall survival in AML patients. SHIP1 may be an interesting candidate for gene therapy.

Targeted PI3K/AKT-hyperactivation induces cell death in chronic lymphocytic leukemia

“…Indeed, B-cell-specific knockout of SHIP1 in mice results in the loss of B-cell tolerance and autoimmune manifestations 69 . Similarly, SHIP1 may act as a tumor suppressor in other tumor entities, including AML and T-ALL, and its inhibition may promote proliferation of pre-malignant cells of other origins 70 . However, our therapeutic approach is based on transient SHIP1 inhibition, and potential proliferative signals to other cells are only present for the limited time of treatment.…”

Ectopic Expression of Hematopoietic SHIP1 in Human Colorectal Cancer

“…Previous research on SHIP1 has concentrated on the effects of SHIP1 in hematopoietic cells, where SHIP1 is endogenously expressed. In these cells, SHIP1 has been shown to function as a tumor suppressor in acute myeloid leukemia due to the reduction of PI3K-AKT signaling [ 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. This role does not predict an upregulation of SHIP1 expression in solid tumors, which, however, is the case.…”

“…Another inositol 5-phosphatase, synaptojanin 2, has also been shown to be responsible for the metastatic potential of breast cancer cells [ 6 ]. These findings prompted us to investigate a putative role of the hematopoietic inositol 5-phosphatase SHIP1 in carcinomas, which shows endogenous expression only in the hematopoietic lineage and therein functions as a negative regulator of hematopoiesis and a suppressor of leukemogenesis [ 7 , 8 , 9 , 10 , 11 , 12 , 13 ].…”

Analysis of the FLVR motif of SHIP1 and its importance for the protein stability of SH2 containing signaling proteins

“…PTEN and SHIP1 are apparently cooperative in suppressing B-cell lymphoma. In contrast, lentiviral mediated overexpression of SHIP1 alone in a xenograft transplantation model of acute myeloid leukemia resulted in significantly prolonged survival of the mice compared to control cohort (Täger et al, 2017). Furthermore, expression of SHIP1 is down regulated by BCR-ABL and SHIP1 is barely detectable in BCR/ABL-positive chronic myeloid leukemia (Sattler et al, 1999).…”

“…The inositol phosphatase SHIP1 (src homology 2 domain-containing inositol phosphatase 1) serves as a negative regulator of the PI3K/AKT signaling pathway. In recent years SHIP1 has also been identified as an important tumor suppressor (Horn et al, 2004;Pedersen et al, 2009;Miletic et al, 2010;Brauer et al, 2012;Ehm et al, 2015, Täger et al, 2017. SHIP1 possesses important functions as a negative regulator of signal transduction in hematopoietic cells.…”