Rogue Cell Communications Lead to Leukemia, Study Finds

Through a series of live-cell single-molecule imaging experiments, researchers at the University of York discovered how rogue communications between cells lead to leukemia, according to a recent study published in Science.

Using super-resolution fluorescent microscopy, researchers studied the way blood stem cells communicated in real time. Cells received instructions from signaling proteins, which bind to a receptor on the surfaces of separate cells. The proteins then transmit a signal instructing the cell how to operate.

“We quantified the dimerization of 3 prototypic class 1 cytokine receptors in the plasma membrane of living cells,” authors stated. They continued, “Spatial and spaciotemporal correlation of individual receptor subunits showed ligand-induces dimerization and revealed that the associated Janus kinase 2 (JAK2) dimerizes through its pseudokinase domain.”

The study marks the first time it has been demonstrated specific receptors on the surface of blood stem cells are linked by cytokines to form pairs, according to a press release.

Researchers hope the discovery will lead to the use of a new molecular mechanism with ligand-induced dimerization as the central switch initiating activation of these receptors. This would contradict the currently held notion of pre-dimerized, inactive receptors activated by a ligand-induced conformational change.

"Our observations led us to a previously unknown mechanism for how individual mutations trigger blood stem cells to start signaling independently of cytokines, causing the normal system to become out of control and leading to diseases like leukemia,” said Ian S. Hitchcock, PhD, an author of the study. "Understanding this mechanism may enable the identification of targets for the development of new drugs."

The study also yielded the additional findings:

• JAK2 PK domains contribute to receptor dimerization
• The oncogenic JAK2 V617F mutation induces ligand-independent receptor dimerization
• Additional molecular determinants contribute to JAK2 V617F-mediated dimerization
• Membrane-proximal amphipathic segment is involved in receptor dimerization
• Additive interactions control the assembly of the signaling complex
• Weak intrinsic receptor dimerization correlates with constitutive activation
• Oncogenic mutations alter and stabilize the receptor dimerization interface

Study results could also have impacts on therapeutic interventions for myeloproliferative neoplasms, other hematological malignancies, and immunological disorders.

“By directly visualizing individual receptors at physiological conditions under the microscope, we were able to resolve a controversy that has preoccupied the field for more than 20 years,” said Jacob Piehler, Phd, a coauthor of the study.

Reference

Wilmes S, Hafer M, Vuorio J, et al. Mechanism of homodimeric cytokine receptor activation and dysregulation by oncogenic mutations. Science. 2020; 367(6478):643-652. doi: 10.1126/science.aaw3242.