PUBLICATION
CD44 loss of function sensitizes AML cells to the BCL-2 inhibitor venetoclax by decreasing CXCL12-driven survival cues
- Authors
- Yu, X., Munoz-Sagredo, L., Streule, K., Muschong, P., Bayer, E., Walter, R.J., Gutjahr, J.C., Greil, R., Concha, M.L., Müller-Tidow, C., Hartmann, T.N., Orian-Rousseau, V.
- ID
- ZDB-PUB-210612-6
- Date
- 2021
- Source
- Blood 138(12): 1067-1080 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Bridged Bicyclo Compounds, Heterocyclic/pharmacology*
- Cell Survival/drug effects
- Cell Survival/genetics
- Chemokine CXCL12*/genetics
- Chemokine CXCL12*/metabolism
- Female
- Humans
- Hyaluronan Receptors*/genetics
- Hyaluronan Receptors*/metabolism
- Leukemia, Myeloid, Acute*/drug therapy
- Leukemia, Myeloid, Acute*/genetics
- Leukemia, Myeloid, Acute*/metabolism
- Loss of Function Mutation*
- Male
- Proto-Oncogene Proteins c-bcl-2*/antagonists & inhibitors
- Proto-Oncogene Proteins c-bcl-2*/genetics
- Proto-Oncogene Proteins c-bcl-2*/metabolism
- Sulfonamides/pharmacology*
- Tumor Cells, Cultured
- PubMed
- 34115113 Full text @ Blood
Citation
Yu, X., Munoz-Sagredo, L., Streule, K., Muschong, P., Bayer, E., Walter, R.J., Gutjahr, J.C., Greil, R., Concha, M.L., Müller-Tidow, C., Hartmann, T.N., Orian-Rousseau, V. (2021) CD44 loss of function sensitizes AML cells to the BCL-2 inhibitor venetoclax by decreasing CXCL12-driven survival cues. Blood. 138(12):1067-1080.
Abstract
Acute myeloid leukemia (AML) has a poor prognosis under the current standard of care. In recent years, venetoclax, a BCL-2 inhibitor, was approved to treat patients, ineligible for intensive induction chemotherapy. Complete remission rates with venetoclax-based therapies are, however, hampered by minimal residual disease (MRD) in a proportion of patients, leading to relapse. MRD is due to leukemic stem cells retained in bone marrow protective environments; activation of the CXCL12/CXCR4 pathway was shown to be relevant to this process. An important role is also played by cell adhesion molecules such as CD44, which has been shown to be crucial for AML development. Here we show that CD44 is involved in CXCL12 promotion of resistance to venetoclax-induced apoptosis in human AML cell lines and AML patient samples which could be abrogated by CD44 knockdown, knockout or blocking with an anti-CD44 antibody. Split-Venus biomolecular fluorescence complementation showed that CD44 and CXCR4 physically associate at the cell membrane upon CXCL12 induction. In the venetoclax-resistant OCI-AML3 cell line, CXCL12 promoted an increase in the proportion of cells expressing high levels of embryonic-stem-cell core transcription factors (ESC-TFs: Sox2, Oct4, Nanog), abrogated by CD44 knockdown. This ESC-TF-expressing subpopulation which could be selected by venetoclax treatment, exhibited a basally-enhanced resistance to apoptosis, and expressed higher levels of CD44. Finally, we developed a novel AML xenograft model in zebrafish, showing that CD44 knockout sensitizes OCI-AML3 cells to venetoclax treatment in vivo. Our study shows that CD44 is a potential molecular target to sensitize AML cells to venetoclax-based therapies.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping