Dissecting infant leukemia developmental origins with a hemogenic gastruloid model

Area of Science:

• Developmental Biology
• Hematopoiesis Research
• Cancer Biology

Background:

• Existing in vitro models of embryonic blood formation lack spatio-temporal accuracy.
• Current models poorly replicate the successive waves of hematopoiesis observed in vivo.

Purpose of the Study:

• To develop an improved in vitro model for studying embryonic hematopoiesis.
• To investigate the origins of infant acute myeloid leukemia (infAML) using this novel model.

Main Methods:

• Generation of a mouse embryonic stem cell (SC)-derived 3D hemogenic gastruloid (haemGx).
• Utilizing the haemGx model to study MNX1-driven infant AML.
• Employing phenotypic, functional, and single-cell transcriptional profiling.

Main Results:

• The haemGx model accurately captures multi-wave blood formation and progenitor specification from hemogenic endothelium (HE).
• Generated hematopoietic progenitors showed short-term engraftment potential in immunodeficient mice.
• Enforced MNX1 expression in haemGx recapitulated patient transcriptional signatures for infAML.

Conclusions:

• The haemGx model offers a powerful new tool for studying normal embryonic hematopoiesis.
• This model provides insights into the origins of MNX1-driven infant acute myeloid leukemia.
• The haemGx system advances research in both developmental blood formation and leukemia biology.