Identifying targeted therapies for CBFA2T3::GLIS2 acute myeloid leukemia

Area of Science:

• Oncology
• Hematology
• Genetics

Background:

• CBFA2T3::GLIS2-positive pediatric acute myeloid leukemia (AML) represents a high-risk subgroup with poor prognosis.
• Identifying novel therapeutic targets is crucial for improving outcomes in this AML subtype.

Purpose of the Study:

• To uncover innovative targeted therapy approaches for CBFA2T3::GLIS2-positive AML.
• To investigate the dependency on JAK2 and mechanisms of resistance to JAK2 inhibitors.

Main Methods:

• Genome-scale CRISPR-Cas9 screening to identify dependencies.
• Doxycycline-inducible JAK2 knockout system for validation.
• CRISPR-Cas9 ruxolitinib anchor screening to identify resistance mechanisms.
• Combination therapy studies with JAK2 and MEK inhibitors in cell lines and patient-derived xenografts (PDXs).

Main Results:

• Genome-scale screening revealed a selective dependency on JAK2 in CBFA2T3::GLIS2 AML.
• JAK2 inhibition impaired proliferation and induced apoptosis in vitro and in vivo.
• MAPK pathway activation, driven by NRAS mutations, emerged as a resistance mechanism to JAK2 inhibitors.
• Combination of ruxolitinib (JAK2 inhibitor) and MEK inhibitors demonstrated synergistic effects and in vivo activity.

Conclusions:

• CBFA2T3::GLIS2 AML is critically dependent on JAK2 signaling.
• MAPK pathway activation confers resistance to JAK2 inhibitors.
• Combination therapy targeting both JAK2 and MAPK pathways offers a potential therapeutic strategy for this poor-prognosis AML subtype.