ERK1/2 Pathway Is Required for Differentiation of AML Triggered by Anti-CD44 Monoclonal Antibodies

Nour Y. Al-Madhoun, Samah Gadhoum, Jasmeen Merzaban

Research output: Contribution to journalArticlepeer-review

Abstract

Abstract Abstract 4334 Acute myeloid leukemia (AML) is a heterogeneous disease characterized by accumulation of immature hematopoietic cells due to a blockage in myeloid differentiation at various stages. Since the current chemotherapy rarely eradicates the leukemic clones entirely, differentiation induction therapy has evolved. Previous experiments have shown that ligation of CD44, a cell surface glycoprotein strongly expressed on all AML cells, with anti-CD44 monoclonal antibodies (mAbs) could reverse the differentiation blockage of leukemic blasts and inhibit their proliferation in most AML subtypes, rendering CD44 a promising target for AML therapy. However, the underlying molecular mechanisms of the induction of differentiation by anti-CD44 mAbs have not been fully elucidated. Here, we investigated the signaling pathways triggered during anti-CD44 mAb (A3D8)-induced granulocytic differentiation of HL60, a human leukemic cell line commonly used as a model of human AML type2/3. Extracellular signal regulated kinase (ERK1/2) pathway plays a major role in the regulation of differentiation and proliferation for myeloid cells and has been reported to be aberrantly activated in AML. In our studies, we observed an increase of ERK1/2 phosphorylation by mitogen-activated ERK kinase (MEK) following A3D8 treatment. The use of U0126 (a MEK inhibitor) significantly abrogated the anti-CD44 induced granulocytic differentiation of HL60 cells, suggesting that ERK1/2 is critical for the induction of differentiation via CD44 in AML-M2/3. Our work provides the first evidence for the importance of the ERK pathway in granulocytic differentiation via CD44 and adds a new argument to the use of CD44 in differentiation therapy of AML. Disclosures: No relevant conflicts of interest to declare.
Original languageEnglish (US)
Pages (from-to)4334-4334
Number of pages1
JournalBlood
Volume120
Issue number21
DOIs
StatePublished - Nov 16 2012

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Immunology
  • Hematology

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