Signalling input from divergent pathways subverts B cell transformation
Lai N Chan1, Mark A Murakami2,3, Mark E Robinson1
1Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, CA, USA.
Nature
|July 24, 2020
Summary
Cancer develops when mutations converge on a single oncogenic pathway, not individually. Reactivating suppressed pathways can reverse transformation and enhance leukemia treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Cancer arises from accumulated genetic mutations.
- Leukemogenesis involves specific oncogenic pathways driving cell transformation.
- B-cell acute lymphoblastic leukemia (B-ALL) is characterized by distinct genetic lesions.
Purpose of the Study:
- To investigate the role of converging oncogenic pathways in B-ALL.
- To understand how divergent pathways affect leukaemogenesis.
- To explore therapeutic strategies targeting oncogenic pathways in B-ALL.
Main Methods:
- Analysis of 1,148 patient-derived B-ALL samples.
- Single-cell mutation and phospho-protein analyses.
- Investigating STAT5 and ERK signaling pathways and their associated transcription factors (MYC, BCL6).
Main Results:
- Leukemia development requires convergence on a single oncogenic pathway characteristic of the cell's differentiation stage.
- Mutations activating STAT5 (pro-B-cell stage) or ERK (pre-B-cell stage) are common but typically segregated into competing clones.
- Reactivation of suppressed divergent pathways reversed transformation, while their deletion accelerated it.
Conclusions:
- Convergence on a principal oncogenic driver is central to leukemia initiation.
- Divergent signaling pathways act as a barrier to transformation.
- Reactivating suppressed divergent pathways offers a novel therapeutic strategy to enhance treatment response in B-ALL, synergizing with inhibition of the principal oncogenic driver.
Related Concept Videos
01:24B Cell Activation and Differentiation
15.5K
The adaptive immune response, a sophisticated defense mechanism, relies on the activation and differentiation of B lymphocytes, or B cells. These processes enable our bodies to mount a tailored response against specific pathogens such as bacteria, free virus particles, toxins, and parasites.
When naive B cells encounter a specific antigen that can bind to the B cell receptor (BCR) on their surface, they undergo sensitization to respond to the antigen's presence. Sensitization begins with...
When naive B cells encounter a specific antigen that can bind to the B cell receptor (BCR) on their surface, they undergo sensitization to respond to the antigen's presence. Sensitization begins with...
15.5K
01:19Interactions Between Signaling Pathways
7.0K
Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
7.0K
01:22Diversity in Cell Signaling Responses
7.4K
The physiological function of a cell and cellular communication are outcomes of a range of extrinsic signals, intracellular signaling pathways, and cellular responses. No two cell types express the same repertoire of signaling components. Receptors are highly selective for their cognate ligands, but once activated, they can alter multiple cellular processes such as DNA transcription, protein synthesis, and metabolic activity.
Graded and Abrupt Responses
Some signaling systems generate...
Graded and Abrupt Responses
Some signaling systems generate...
7.4K
01:31The Intrinsic Apoptotic Pathway
7.9K
Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
7.9K
01:22T Cell Activation and Clonal Selection
14.3K
T cells are integral to our adaptive immune system, recognizing and effectively responding to foreign antigens. T cell activation and clonal selection are pivotal in orchestrating this immune response. This article elucidates these mechanisms, detailing the roles of cluster of differentiation (CD) markers, major histocompatibility complex (MHC) molecules, costimulatory signals, and the process of clonal selection.
Naive T cells that have not yet encountered an antigen express two primary CD...
Naive T cells that have not yet encountered an antigen express two primary CD...
14.3K
01:23Cells of the Adaptive Immune Response
8.2K
The T and B lymphocytes of the adaptive immune system develop from common lymphoid progenitor cells in the bone marrow. These progenitors give rise to precursors that eventually develop into both T and B lymphocytes. As these precursors mature, they gain the ability to detect and respond to foreign antigens in the body, a process known as immunocompetence. Additionally, these precursors acquire self-tolerance, a process that ensures they do not react to self-antigens. This intricate system...
8.2K