TY - JOUR
T1 - Hitting the bullseye with a nonlethal payload
T2 - Resistance in CD123-positive malignancies
AU - Gondek, Lukasz P.
N1 - Funding Information:
The author acknowledges support from the NIH (grants K08HL136894 and R21HL143096).
Publisher Copyright:
Copyright: © 2019, American Society for Clinical Investigation.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - The interleukin 3 receptor (CD123) is a transmembrane protein that is absent or hardly expressed on normal hematopoietic stem cells, but highly expressed on the surface of cancer cells in several hematologic malignancies. In this issue of the JCI, Togami et al. investigated the mechanism of resistance to the recently approved anti-CD123 agent tagraxofusp, which consists of interleukin 3 fused to a truncated diphtheria toxin (DT) molecule. The authors demonstrated that loss of the intracellular target for DT, diphthamide, a conservative modification of histidine 715 in eukaryotic elongation factor 2, resulted in tagraxofusp resistance. Specifically, hypermethylation of the DPH1 gene, encoding a key enzyme in diphthamide synthesis, resulted in diphthamide loss. Notably, treatment with a DNA hypomethylating agent restored DPH1 expression and resensitized cells to tagraxofusp. The recognition of this resistance mechanism may have important clinical implications and lead to the development of more effective multiagent therapies.
AB - The interleukin 3 receptor (CD123) is a transmembrane protein that is absent or hardly expressed on normal hematopoietic stem cells, but highly expressed on the surface of cancer cells in several hematologic malignancies. In this issue of the JCI, Togami et al. investigated the mechanism of resistance to the recently approved anti-CD123 agent tagraxofusp, which consists of interleukin 3 fused to a truncated diphtheria toxin (DT) molecule. The authors demonstrated that loss of the intracellular target for DT, diphthamide, a conservative modification of histidine 715 in eukaryotic elongation factor 2, resulted in tagraxofusp resistance. Specifically, hypermethylation of the DPH1 gene, encoding a key enzyme in diphthamide synthesis, resulted in diphthamide loss. Notably, treatment with a DNA hypomethylating agent restored DPH1 expression and resensitized cells to tagraxofusp. The recognition of this resistance mechanism may have important clinical implications and lead to the development of more effective multiagent therapies.
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U2 - 10.1172/JCI132443
DO - 10.1172/JCI132443
M3 - Review article
C2 - 31609247
AN - SCOPUS:85074444725
SN - 0021-9738
VL - 129
SP - 4590
EP - 4592
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 11
ER -