Inducible MLL-AF9 Expression Drives an AML Program during Human Pluripotent Stem Cell-Derived Hematopoietic...

Area of Science:

• Hematology
• Cancer Biology
• Stem Cell Biology

Background:

• The MLL-AF9 fusion protein, resulting from a t(9;11) translocation, is a key driver in approximately 25% of pediatric de novo acute myeloid leukemia (AML).
• Understanding the precise gene programs regulated by MLL-AF9 during early hematopoiesis is crucial but challenging.

Purpose of the Study:

• To develop a human induced pluripotent stem cell (hiPSC) model for studying MLL-AF9's oncogenic effects on hematopoietic development.
• To identify MLL-AF9-associated gene expression profiles and epigenetic changes in early hematopoiesis and pre-leukemic states.

Main Methods:

• Generation of a doxycycline-inducible hiPSC model for controlled MLL-AF9 expression.
• Utilizing single-cell RNA-sequencing (scRNA-seq) to analyze cellular changes during hematopoietic differentiation.
• Comparison of gene profiles with primary MLL-AF9 AML samples.

Main Results:

• MLL-AF9 expression disrupted early myelomonocytic development in hiPSC-derived hematopoiesis.
• Identified core MLL-AF9-associated genes, including novel factors, that are conserved in primary MLL-AF9 AML.
• scRNA-seq revealed an increase in CD34+ hematopoietic progenitor and granulocyte-monocyte progenitor-like cells upon MLL-AF9 activation.

Conclusions:

• The hiPSC model provides a robust platform for dissecting MLL-AF9's role in leukemogenesis under controlled conditions.
• The identified core gene set offers potential therapeutic targets for personalized strategies in MLL-AF9 AML.
• This system facilitates the exploration of novel therapeutic strategies for a disease lacking effective precision medicine.