The CD44 surface antigen is highly expressed on AML cells. We previously reported that its ligation with specific monoclonal antibodies (mAbs) triggers terminal differentiation of leukemic blasts in all AML subtypes. This raised the perspective of developing a CD44-targeted therapy that would be efficient in all AML subtypes, including the monoblastic one (AML-M5) in which, in the absence of specific genetic abnormalities, no targeted therapy is being developed. Here we investigated the molecular mechanism responsible for the CD44-induced differentiation in primary AML-M5 blast samples (n=13). Firstly, by using cDNA arrays, we show that CD44 ligation:

  1. activates a burst of cytokine and chemokine genes, through the p38MAPK pathway, indicating that normal CD44 pathways are functional in AML-M5 blasts; and

  2. modulates the gene expression of enzymes, surface proteins and transcription factors as in normal monopoiesis.

Secondly, by using functional inhibitors, we demonstrate that the differentiation of CD44-ligated AML-M5 blasts is mediated by IL-1b, GM-CSF and IL-8. These proteins act locally, through an autocrine/paracrine pathway, suggesting that most of the drawbacks often provoked by their systemic injection should be very attenuated. Together, these results provide new support for the development of a CD44-targeted differentiation therapy in acute monoblastic leukemia.

Topics:
cd44 antigens, granulocyte-macrophage colony-stimulating factor, homing-associated cell adhesion molecule, interleukin-1, interleukin-8, leukemia, ligation, precipitating factors, recombinant granulocyte-macrophage colony-stimulating factors, chemokines

Disclosure: No relevant conflicts of interest to declare.

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2006, The American Society of Hematology
2006
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