FLT3 ligand causes autocrine signaling in acute myeloid leukemia cells

Rui Zheng, Mark Levis, Obdulio Piloto, Patrick Brown, Brenda R. Baldwin, Norbert C. Gorin, Miloslav Beran, Zhenping Zhu, Dale Ludwig, Dan Hicklin, Larry Witte, Yiwen Li, Donald Small

Research output: Contribution to journalArticle

Abstract

The FLT3 receptor tyrosine kinase is highly expressed in most acute leukemias and frequently mutated in acute myeloid leukemia (AML). The mutated form of the receptor is constitutively activated and known to play an important role in AML, but the activation state of the overexpressed wild-type (wt) receptor is, at present, unknown. In this study, we examined the activation state of the wildtype receptor in AML. We found that the wild-type receptor was constitutively phosphorylated/activated in 8 of 12 primary AML samples and 4 of 13 leukemia cell lines. To explain why wtFLT3 is often activated, we investigated the expression of its ligand, FL, by these same cells. Coexpression of FL with FLT3 was a universal finding in both primary AML samples and leukemic-derived cell lines. To further prove that autocrine signaling was accounting for the activation, we showed that conditioned media but not fresh media was able to activate FLT3. In addition, an antibody that blocks binding of ligand to the receptor blocks FLT3 activation. Finally, depletion of FL from conditioned media is able to block the activation of FLT3. Taken together, these findings represent strong evidence that wtFLT3 is often constitutively activated in AML and thus, like its mutated form, might contribute to the altered signaling that characterizes leukemogenesis.

Original languageEnglish (US)
Pages (from-to)267-274
Number of pages8
JournalBlood
Volume103
Issue number1
DOIs
StatePublished - Jan 1 2004

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Zheng, R., Levis, M., Piloto, O., Brown, P., Baldwin, B. R., Gorin, N. C., Beran, M., Zhu, Z., Ludwig, D., Hicklin, D., Witte, L., Li, Y., & Small, D. (2004). FLT3 ligand causes autocrine signaling in acute myeloid leukemia cells. Blood, 103(1), 267-274. https://doi.org/10.1182/blood-2003-06-1969