NCAM1 (CD56) promotes leukemogenesis and confers drug resistance in AML.

Abstract

Neural cell adhesion molecule 1 (NCAM1; CD56) is expressed in up to 20% of acute myeloid leukemia (AML) patients. NCAM1 is widely used as a marker of minimal residual disease; however, the biological function of NCAM1 in AML remains elusive. In this study, we investigated the impact of NCAM1 expression on leukemogenesis, drug resistance, and its role as a biomarker to guide therapy. Beside t(8;21) leukemia, NCAM1 expression was found in most molecular AML subgroups at highly heterogeneous expression levels. Using complementary genetic strategies, we demonstrated an essential role of NCAM1 in the regulation of cell survival and stress resistance. Perturbation of NCAM1 induced cell death or differentiation and sensitized leukemic blasts toward genotoxic agents in vitro and in vivo. Furthermore, Ncam1 was highly expressed in leukemic progenitor cells in a murine leukemia model, and genetic depletion of Ncam1 prolonged disease latency and significantly reduced leukemia-initiating cells upon serial transplantation. To further analyze the mechanism of the NCAM1-associated phenotype, we performed phosphoproteomics and transcriptomics in different AML cell lines. NCAM1 expression strongly associated with constitutive activation of the MAPK-signaling pathway, regulation of apoptosis, or glycolysis. Pharmacological inhibition of MEK1/2 specifically inhibited proliferation and sensitized NCAM1+ AML cells to chemotherapy. In summary, our data demonstrate that aberrant expression of NCAM1 is involved in the maintenance of leukemic stem cells and confers stress resistance, likely due to activation of the MAPK pathway. Targeting MEK1/2 sensitizes AML blasts to genotoxic agents, indicating a role for NCAM1 as a biomarker to guide AML treatment.

• Authors: Daniel Sasca, Jakub Szybinski, Andrea Schüler, Viral Shah, Jan Heidelberger, Patricia S Haehnel, Anna Dolnik, Oliver Kriege, Eva-Marie Fehr, Wolf H Gebhardt, George Reid, Claudia Scholl, Matthias Theobald, Lars Bullinger, Petra Beli, Thomas Kindler
• Journal: Blood (Blood) Vol. 133 Issue 21 Pg. 2305-2319 (05 23 2019) ISSN: 1528-0020 [Electronic] United States
• PMID: 30814062 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 by The American Society of Hematology.

Chemical References

• Biomarkers, Tumor
• CD56 Antigen
• NCAM1 protein, human
• Ncam1 protein, mouse
• Neoplasm Proteins

Topics

• Animals
• Apoptosis (genetics)
• Biomarkers, Tumor (genetics, metabolism)
• Blast Crisis (genetics, metabolism, pathology, therapy)
• CD56 Antigen (genetics, metabolism)
• Drug Resistance, Neoplasm
• Female
• Glycolysis (genetics)
• HL-60 Cells
• Humans
• K562 Cells
• Leukemia, Myeloid, Acute (genetics, metabolism, pathology, therapy)
• MAP Kinase Signaling System (genetics)
• Male
• Mice
• Mice, Inbred NOD
• Mice, Knockout
• Neoplasm Proteins (genetics, metabolism)