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mTORC1 activity is essential for erythropoiesis and B cell lineage commitment

Natasha Malik1, Karen M Dunn1, Jennifer Cassels1

  • 1Institute of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.

Scientific Reports
|November 16, 2019
PubMed

Insights

Mechanistic target of rapamycin complex 1 (mTORC1) is crucial for blood cell development. Inhibiting mTORC1 disrupts red blood cell and B cell production, highlighting its essential role in hematopoietic lineage commitment.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Hematology

Background:

  • The mechanistic target of rapamycin (mTOR) pathway, specifically mTOR complex 1 (mTORC1), is a key regulator of cellular functions including protein synthesis, cell proliferation, and apoptosis.
  • Understanding the role of mTORC1 in hematopoietic stem cell differentiation is critical for comprehending blood cell development and potential therapeutic interventions.

Purpose of the Study:

  • To investigate the specific role of mTORC1 in hematopoietic lineage commitment using genetic knockout mouse models and cell lines.
  • To delineate the impact of mTORC1 deficiency on erythropoiesis and B lymphopoiesis.

Main Methods:

  • Utilized Mx1-cre and Vav-cre expression systems to generate Raptor-deficient (mTORC1) mouse models.
  • Assessed developmental and cellular phenotypes in knockout mice, including survival rates, erythropoiesis, and B cell development.
  • Confirmed findings using K562 cell differentiation assays and mTOR inhibitors in vitro.
  • Investigated the opposing role of mTORC2 by analyzing Rictor-deficient progenitor cells.

Main Results:

  • Vav-cre+Raptorfl/fl mice exhibited embryonic lethality due to severe aberrations in erythropoiesis, with an arrest at the megakaryocyte-erythrocyte progenitor stage.
  • Raptor-deficient mice showed a significant block in B cell lineage commitment.
  • These defects were recapitulated in adult Mx1-cre+Raptorfl/fl mice upon induction, confirming the essential role of mTORC1 in erythrocyte and B lineage commitment.
  • Expression of key regulators GATA1, GATA2, and PAX5 was dysregulated in the absence of mTORC1.
  • In vitro studies demonstrated that mTOR inhibition reduced K562 cell differentiation towards red blood cells (RBCs).
  • Conversely, Rictor deficiency (mTORC2) led to enhanced RBC colony formation, indicating an opposing role for mTORC2.

Conclusions:

  • mTORC1 is critically important for regulating hematopoietic cell lineage commitment, particularly for erythropoiesis and B lymphopoiesis.
  • mTORC1 signaling is essential for the proper development of red blood cells and B cells.
  • mTORC2 appears to have an antagonistic role in RBC development compared to mTORC1.

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