Aberrant Mer receptor tyrosine kinase expression contributes to leukemogenesis in acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) continues to be extremely difficult to treat successfully, and the unacceptably low overall survival rates mandate that we assess new potential therapies to ameliorate poor clinical response to conventional therapy. Abnormal tyrosine kinase activation in AML has been associated with poor prognosis and provides strategic targets for novel therapy development. We found that Mer receptor tyrosine kinase was over-expressed in a majority of pediatric (29/36, 80%) and adult (10/10, 100%) primary AML patient blasts at the time of diagnosis, and 100% of patient samples at the time of relapse. Mer was also found to be expressed in 12 of 14 AML cell lines (86%). In contrast, normal bone marrow myeloid precursors expressed little to no Mer. Following AML cell line stimulation with Gas6, a Mer ligand, we observed activation of prosurvival and proliferative signaling pathways, including phosphorylation of ERK1/2, p38, MSK1, CREB, ATF1, AKT and STAT6. To assess the phenotypic role of Mer in AML, two independent short-hairpin RNA (shRNA) constructs were used to decrease Mer expression in the AML cell lines Nomo-1 and Kasumi-1. Reduction of Mer protein levels significantly increased rates of myeloblast apoptosis two to threefold in response to serum starvation. Furthermore, myeloblasts with knocked-down Mer demonstrated decreased colony formation by 67–87%, relative to control cell lines (P<0.01). NOD-SCID-gamma mice transplanted with Nomo-1 myeloblasts with reduced levels of Mer had a significant prolongation in survival compared with mice transplanted with the parental or control cell lines (median survival 17 days in parental and control cell lines, versus 32–36 days in Mer knockdown cell lines, P<0.0001). These data suggest a role for Mer in acute myeloid leukemogenesis and indicate that targeted inhibition of Mer may be an effective therapeutic strategy in pediatric and adult AML.

Mer receptor tyrosine kinase is a therapeutic target in pre–B-cell acute lymphoblastic leukemia

“…14 Mer activates antiapoptotic signaling proteins, including AKT and ERK1/2, [15][16][17] and promotes tumorigenic phenotypes in several other tumor types, including non-small-cell lung cancer, 18 melanoma, 19 and acute myeloid leukemia. 20 Here, we present data demonstrating increased Mer protein in E2A-PBX1…”

“…15,17,20 Here, we describe Mer-dependent modification of these signaling pathways and provide the first demonstration of p38 MAPK activation downstream of Mer in human B-ALL cells.…”

Molecular Pathways: MERTK Signaling in Cancer

“…MERTK knockdown by short hairpin RNA (shRNA) resulted in decreased levels of phospho-STAT5 and phospho-Erk. In addition, in acute myeloid leukemia cells that did not express Axl or Tyro3, Gas6 activated MERTK and resulted in the phosphorylation and activation of Erk1/2, p38, MSK1, cAMPresponsive element binding protein (CREB), activating transcription factor 1 (ATF1), Akt, and STAT6 (49). shRNA knockdown of MERTK reduced the activation of p38, Erk, and CREB, further strengthening these signaling findings.…”

“…In T-cell acute lymphoblastic leukemia, shRNA against MERTK resulted in increased apoptosis, decreased methylcellulose colony formation, increased sensitivity to cytotoxic chemotherapies, and delayed disease onset with increased survival in a murine leukemia model (9,10). Similarly, in acute myeloid leukemia, MERTK inhibition resulted in increased apoptosis, decreased colony formation, and increased survival in a mouse model (49). In glioblastoma, MERTK shRNA increased apoptosis and autophagy, decreased colony formation, increased chemosensitivity, altered morphology, and decreased migration (16)(17)(18).…”

Mer tyrosine kinase promotes the survival of t(1;19)-positive acute lymphoblastic leukemia (ALL) in the central nervous system (CNS)

“…[5][6][7] Mer expression has been shown on macrophages, natural killer (NK) cells, dendritic cells, megakaryocytes, and platelets, 8 but it is not known to be present on normal T and B lymphocytes at any stage of differentiation. Aberrant Mer expression was detected in not only acute myeloid leukemia (AML), 9 but also lymphocytic malignancies as T-cell acute lymphoblastic leukemia (T-ALL). 10 Studies overexpressing Mer in fibroblasts found that it can induce extracellular signalregulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), p38, nuclear factor-kB (NF-kB) and enhance cell survival via phosphatidylinositol 3-kinase (PI3K)/AKT.…”