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Oncogene-independent BCR-like signaling adaptation confers drug resistance in Ph-like ALL
- Source :
- J Clin Invest
- Publication Year :
- 2020
- Publisher :
- American Society for Clinical Investigation, 2020.
-
Abstract
- Children and adults with Philadelphia chromosome–like B cell acute lymphoblastic leukemia (Ph-like B-ALL) experience high relapse rates despite best-available conventional chemotherapy. Ph-like ALL is driven by genetic alterations that activate constitutive cytokine receptor and kinase signaling, and early-phase trials are investigating the potential of the addition of tyrosine kinase inhibitors (TKIs) to chemotherapy to improve clinical outcomes. However, preclinical studies have shown that JAK or PI3K pathway inhibition is insufficient to eradicate the most common cytokine receptor–like factor 2–rearranged (CRLF2-rearranged) Ph-like ALL subset. We thus sought to define additional essential signaling pathways required in Ph-like leukemogenesis for improved therapeutic targeting. Herein, we describe an adaptive signaling plasticity of CRLF2-rearranged Ph-like ALL following selective TKI pressure, which occurs in the absence of genetic mutations. Interestingly, we observed that Ph-like ALL cells have activated SRC, ERK, and PI3K signaling consistent with activated B cell receptor (BCR) signaling, although they do not express cell surface μ-heavy chain (μHC). Combinatorial targeting of JAK/STAT, PI3K, and “BCR-like” signaling with multiple TKIs and/or dexamethasone prevented this signaling plasticity and induced complete cell death, demonstrating a more optimal and clinically pragmatic therapeutic strategy for CRLF2-rearranged Ph-like ALL.
- Subjects :
- 0301 basic medicine
MAPK/ERK pathway
B-cell receptor
Receptors, Antigen, B-Cell
Biology
Dexamethasone
Cell Line
Mice
03 medical and health sciences
0302 clinical medicine
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
Animals
Humans
Protein Kinase Inhibitors
PI3K/AKT/mTOR pathway
breakpoint cluster region
General Medicine
Neoplasm Proteins
030104 developmental biology
030220 oncology & carcinogenesis
Cancer research
Signal transduction
Cytokine receptor
Tyrosine kinase
Signal Transduction
Research Article
Proto-oncogene tyrosine-protein kinase Src
Subjects
Details
- ISSN :
- 15588238 and 00219738
- Volume :
- 130
- Database :
- OpenAIRE
- Journal :
- Journal of Clinical Investigation
- Accession number :
- edsair.doi.dedup.....afce6119cd0b0818456c2d89f7f812b2