Disruption of HOX activity leads to cell death that can be enhanced by the interference of iron uptake in malignant B cells.
The HOX genes encode a family of transcription factors that are dysregulated in several malignancies and have been implicated in oncogenesis and cancer cell survival. Disruption of HOX protein function using the peptide HXR9 has shown anti-tumor effects against melanoma, lung cancer and renal cancer. In this report, we evaluated the expression of all 39 HOX genes in a panel of six malignant B-cell lines, including multiple myeloma cells and found different levels of expression of HOX family members suggesting that they also have a role in malignant B-cell survival. We show that disrupting HOX function using the peptide HXR9 induces significant cytotoxicity in the entire panel of cell lines. Importantly, we found that the cytotoxic effects of HXR9 can be enhanced by combining it with ch128.1Av, an antibody-avidin fusion protein specific for the human transferrin receptor 1 (CD71). Iron starvation induced by the fusion protein contributes to the enhanced effect and involves, at least in part, the induction of a caspase-independent pathway. These results show the relevance of HOX proteins in malignant B-cell survival and suggest that our therapeutic strategy may be effective in the treatment of incurable B-cell malignancies such as multiple myeloma.
Daniels
T R
TR
Division of Surgical Oncology, Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1782, USA.
Neacato
I I
II
Rodríguez
J A
JA
Pandha
H S
HS
Morgan
R
R
Penichet
M L
ML
D016923:Cell Death / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005801:Genes, Homeobox; D006801:Humans; D007501:Iron / Q000378:metabolism*; D016393:Lymphoma, B-Cell / Q000378:metabolism / Q000473:pathology*; D016133:Polymerase Chain Reaction
D007501:Iron