Editors' ChoiceLeukemia

Leukemia: The Master Vampire

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Science Translational Medicine  23 Nov 2011:
Vol. 3, Issue 110, pp. 110ec189
DOI: 10.1126/scitranslmed.3003456

There’s something about vampires that people find irresistible, as attested by the seemingly never-ending stream of movies, books, games, and television shows that feature these creatures of the night. Part of this fascination may stem from vampires’ need to drink blood to survive—the mere thought of stealing something so essential to life fills even the staunchest with horror. Yet a more insidious bloodsucker plagues the real world: cancer. Cancer cells need blood flow to survive, and solid tumors promote new blood vessel growth, in part through the actions of vascular endothelial growth factor (VEGF). However, the role of VEGF in the pathophysiology of hematologic malignancies such as leukemia is not well characterized. Now, Markovic et al. have demonstrated that secretion of VEGF by leukemia cells involves the activation of the FMS-like tyrosine kinase-3 (FLT-3) pathway.

Wild-type FLT-3 contributes to the regulation of survival and proliferation of normal hematopoietic stem and progenitor cells. FLT-3 is mutated in approximately one-third of acute myeloid leukemia (AML) patients and is associated with high relapse rate and poor prognosis. Therefore, Markovic et al.assessed cell surface FLT-3 and FLT-3 ligand (FL)–induced VEGF expression in a series of ex vivo–cultured pediatric acute lymphoblastic leukemia (ALL) xenograft lines that expressed different amounts of FLT-3 on their cell surfaces as well as in an established AML cell line that expressed a constitutively active FLT-3 because of an internal tandem duplication. They found that VEGF secretion strongly correlated with FLT-3 cell surface expression, and addition of FL induced a significant increase in VEGF secretion. A small molecule FLT-3 inhibitor, an antibody that blocked ligand binding, and siRNA-mediated receptor down-regulation all resulted in a decrease in VEGF secretion. Furthermore, the researchers showed that FLT-3 was more likely to induce VEGF secretion through the MAPK (mitogen-activated protein kinase) pathway and involve ERK1/2 (extracellular signal–regulated kinase–1 and –2) phosphorylation than through AKT (protein kinase B) or STAT5 (signal transducer and activator of transcription-5) mediated signaling.

This study is based on a small sample size of xenograft models; however, these results, when considered in the context of the substantial clinical relevance of FLT-3 and VEGF in leukemia, bring to daylight the importance of innovation of new strategies for treatment of acute leukemias with FLT-3 mutations. These studies may someday help put a stake through the heart of these vampiric leukemias.

A. Markovic et al., Induction of vascular endothelial growth factor secretion by childhood acute lymphoblastic leukemia cells via the FLT-3 signaling pathway. Mol. Cancer Ther. 14 November 2011 (10.1158/1535-7163.MCT-11-0503). [Abstract]

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