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Details

Autor(en) / Beteiligte
Titel
NCAM1 (CD56) promotes leukemogenesis and confers drug resistance in AML
Ist Teil von
  • Blood, 2019-05, Vol.133 (21), p.2305-2319
Ort / Verlag
Elsevier Inc
Erscheinungsjahr
2019
Link zum Volltext
Quelle
Alma/SFX Local Collection
Beschreibungen/Notizen
  • 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. •Aberrant NCAM1 expression confers drug resistance in AML.•Expression of NCAM1 activates the MAPK–extracellular signal-regulated kinase pathway and renders cells sensitive to MEK inhibitors. [Display omitted]
Sprache
Englisch
Identifikatoren
ISSN: 0006-4971, 1528-0020
eISSN: 1528-0020
DOI: 10.1182/blood-2018-12-889725
Titel-ID: cdi_crossref_primary_10_1182_blood_2018_12_889725

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