Acquired JAK2 mutations confer resistance to JAK inhibitors in cell models of acute lymphoblastic leukemia

Area of Science:

• Hematology
• Oncology
• Molecular Biology

Background:

• Ruxolitinib (rux) is being investigated in Phase II trials for high-risk JAK2-rearranged (JAK2r) B-cell acute lymphoblastic leukemia (B-ALL).
• Therapeutic resistance to targeted inhibitors is a significant challenge in cancer treatment.

Purpose of the Study:

• To investigate mechanisms of acquired resistance to JAK inhibitors in JAK2r B-ALL.
• To understand how specific mutations in JAK2 affect drug sensitivity.

Main Methods:

• Generation of a murine pro-B cell model with acquired resistance to JAK inhibitors.
• Identification of mutations in the JAK2 ATP/rux binding site, including JAK2 p.G993A.
• In vitro testing of JAK inhibitor efficacy against JAK2r B-ALL with specific mutations.
• Computational modeling to elucidate resistance mechanisms.

Main Results:

• Acquired resistance to multiple JAK inhibitors was associated with mutations in the JAK2 ATP/rux binding site.
• The JAK2 p.G993A mutation conferred resistance to six type-I JAK inhibitors and one type-II JAK inhibitor (CHZ-868).
• Computational modeling suggested JAK2 p.G993A facilitates drug-resistant JAK2 activation by altering the activation loop mobility.

Conclusions:

• Emergence of JAK2 mutations, such as p.G993A, is a key mechanism of resistance to JAK inhibitors in JAK2r B-ALL.
• Monitoring for mutation emergence is critical for effective treatment strategies.
• Findings may guide future drug design and therapeutic development for high-risk B-ALL patients.