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.

Expression Patterns of Coagulation Factor XIII Subunit A on Leukemic Lymphoblasts Correlate with Clinical Outcome and Genetic Subtypes in Childhood B-cell Progenitor Acute Lymphoblastic Leukemia

“…These data suggested that the three different FXIII-A expression profiles defined by FC might characterize novel subgroups of pediatric BCP-ALL [ 32 ]. Similar associations between expression intensity of biomarkers both at the mRNA and protein levels and clinical relevance have been observed to exist in T-ALL and in AML [ 33 , 34 ].…”

Identification of lncRNA–miRNA–mRNA regulatory network associated with epithelial ovarian cancer cisplatin‐resistant

“…Interestingly, a recent study reported miR-7-5p has a role in regulating oxaliplatin, a platinum reagent, resistant in hepatocellular carcinoma (Hu, Yang, Li, & Zeng, 2018). In addition, miR-29a-3p was reported to regulate the response of chronic myeloid leukemia cell to tyrosine kinase inhibitor (Salati et al, 2017 and COL4A1 were associated with chemoresistant in human cancers (Gao et al, 2019;Huang, Gu, Sun, & Gao, 2018;Huy et al, 2018;Ju et al, 2017;Li et al, 2019;Ma et al, 2017;Sasca et al, 2019;Yadav, Kumar, Varshney, & Yadava, 2019).…”

Retracted Article: Long non-coding RNA KCNQ1OT1 regulates cell proliferation, apoptosis and chemo-sensitivity through modulating the miR-186-5p/NCAM1 axis in acute myeloid leukemia cells

“…16 It is reported that NCAM1 has high expression in natural killer (NK) cells and AML patients. 17,18 Moreover, NCAM1 induces leukemogenesis and confers drug resistance to AML cells, 18,19 revealing a role of NCAM1 as a biomarker for the therapy of AML patients. Therefore, NCAM1 plays crucial role in AML cells.…”