A role for RTKs in Hodgkin lymphoma

Thomas Wirth

Comment on Renné et al, page 4051

Activated RTK signaling is associated with oncogenesis. Renné and colleagues now describe both expression and activation of several members of the RTK family in Hodgkin lymphoma.

Our awareness of the link between activated receptor tyrosine kinase (RTK) signaling and oncogenesis is about as old as our conceptual understanding of the molecular biology of cancer. Inspired by data revealed from expression profiling approaches, Renné and colleagues describe both expression and activation of several members of the RTK family in classic Hodgkin lymphoma. This not only hints at novel mechanisms contributing to lymphomagenesis but also identifies potential targets for therapeutic intervention.

Activating mutations in RTKs resulting in constitutive signaling have been implicated and were finally shown to be responsible for tumorigenesis about 20 years ago. Although initially predominantly associated with carcinomas, the role of activating RTK mutations is now also clear for a variety of leukemias, such as fetal liver tyrosine kinase 3 (FLT3) mutations in acute myeloid leukemias and c-kit mutations in mast-cell malignancies. RTKs have attracted major attention not only as causative agents but also consequently as target structures for development of highly selective drugs.1 The small-molecule drug imatinib mesylate (Gleevec) not only inhibits the cytoplasmic bcr/abl (breakpoint cluster region/abelson virus protooncogene) tyrosine kinase causative for chronic myeloid leukemia (CML) but also inhibits RTKs such as platelet-derived growth factor receptor A (PDGFRA) and c-kit. Its therapeutic potential for myeloid malignancies other than CML is currently under investigation.2

In this issue of Blood, Renné and colleagues, following up on their previous expression profiling experiment,3 investigated the expression of RTK family members in classic Hodgkin lymphoma (cHL) cell lines and primary cases. They demonstrate that 6 RTK family members, namely PDGFRA, discoidin domain receptor 2 (DDR2), EphrinB1 (EPHB1), recepteur d' origine nantais (RON), tyrosine receptor kinase A (TRKA), and TRKB, are expressed/coexpressed in a significant proportion of primary cHL cases. In addition, by using antibodies recognizing phosphorylated RTKs they found evidence for activated PDGFRA and TRKA/B signaling. They analyzed the coding sequences of all 6 RTK members in 4 cHL-derived cell lines, yet no indication of specific activating receptor mutations was obtained. However, they identified RTK ligand expression in the HL infiltrates. Whereas expression of DDR2 and TRKA ligands (collagen type I and nerve growth factor [NGF]) were found in sclerotic bands and infiltrating granulocytes, respectively, PDGFA and EphrinB1 expression was typically associated with Hodgkin/Reed-Sternberg (HRS) cells coexpressing the corresponding receptor. This indicates that the former receptors are likely to be triggered in a paracrine fashion, whereas the latter respond to autocrine stimulation.

The contribution of RTK expression and signaling to cHL pathology is not clarified yet. One of the cHL-derived cell lines used in the study (KMH2), which coexpresses both PDGFA and PDGFRA, showed some sensitivity to imatinib. However, given that cHL cells and cell lines simultaneously express several RTKs, interfering with a single signaling pathway might not be sufficient to completely block proliferation. Either a combination of tyrosine kinase inhibitors or interference with a common downstream signaling component (eg, Ras, Raf) might be a useful therapeutic strategies in treatment of cHL. ▪