The cells, derived from a B-cell acute lymphoblastic leukemia cell line, can be easily converted into human macrophage-like cells with 100% efficiency in just few days, recapitulating human macrophage function and biology better and more conveniently than existing model systems.
They can be used for basic research and drug development purposes in relation to auto-inflammation, neurodegeneration, cardiovascular diseases and cancer (immuno-oncology).
Technology:
The myeloid-specific transcription factor C/EBPa converts immature and mature murine B lymphoid-lineage cells into functional myeloid-lineage monocytes/macrophages (Cell Stem Cell 5 (2009) 554-566). Based on this transdifferentation principle in murine cells, CRG scientists from the Graf Group created a tumorigenic, RCH-ACV derived B-cell acute lymphoblastic leukemia cell line that stably expresses C/EBPa under the control of estrogen receptor. Upon induction with b-estradiol or tamoxifen, the cells rapidly and efficiently transdifferentiate into functional, non-tumorigenic monocytes/macrophages. These have an impaired ability to produce tumors in vivo, providing proof of principle for a new therapeutic strategy to treat B cell leukemias and lymphomas. In addition, once transdifferentiated, the monocytes contain an inflammasome machinery, and respond to LPS, exactly as human peripheral blood monocyte/macrophage cells (PBMCs) and distinct from murine PBMCs and the established and widely-used monocyte/macrophage THP-1 model cell line.
This transdifferentiation system is thus a unique, multifunctional and highly translational tool to study immune modulation mediated by macrophages, and to screen for compounds inducers of B-cell transdifferentiation, or that relate to macrophage function and biology (e.g. that modulate IL-1β production, the inflammasome, or that induce macrophage polarization, all of which have deep implications in health and disease, including cancer). A subclonal cell line expressing a reporter system where the lysozyme promotor is fused with a dsRed reporter and turn red during B to macrophage transdifferentiation is also available for faster and clearer read-out in high-content screening.
Advantages:
• Far more relevant to human monocyte/macrophage function and biology than the THP-1 cells commonly used.
• Much more convenient for in vitro studies than primary, donor-derived peripheral mononuclear cells.
• Versatile: suited to validate and screen for compounds inducers of B-cell transdifferentiation, or that modulate macrophage function and biology in relation to a number of diseases (e.g. auto-inflammatory, neurodegenerative, cardiovascular and cancer).
• Subclone available for high-content screening.
References:
1. Rapino et al. C/EBPa Induces Highly Efficient Macrophage Transdifferentiation of B Lymphoma and Leukemia Cell Lines and Impairs Their Tumorigenicity. Cell Reports 3 (2013) 1153–1163.
2. Gaidt et al. Human Monocytes Engage an Alternative Inflammasome Pathway. Immunity 44 (2016) 1–14.
