Signalling thresholds and negative B-cell selection in acute lymphoblastic leukaemia

Area of Science:

• Immunology
• Oncology
• Cell Signaling

Background:

• B cells undergo negative selection if their B-cell antigen receptor (BCR) signaling is too weak or too strong.
• Acute lymphoblastic leukemia (ALL) cells with the BCR-ABL1 tyrosine kinase mimic constitutively active pre-BCR signaling.
• Current ALL therapies target BCR-ABL1 inhibitors to suppress signaling below a survival threshold.

Purpose of the Study:

• To test if targeted hyperactivation of BCR signaling above a maximum threshold can eliminate ALL cells.
• To investigate if this approach engages a deletional checkpoint for self-reactive B cells.

Main Methods:

• Testing proximal pre-BCR signaling components in mouse BCR-ABL1 ALL cells.
• Investigating the role of Syk tyrosine kinase activity in ALL cell death.
• Analyzing the expression and function of inhibitory receptors (PECAM1, CD300A, LAIR1) in patient-derived ALL cells.
• Utilizing a small-molecule inhibitor of INPP5D (SHIP1).

Main Results:

• Incremental increases in Syk tyrosine kinase activity were sufficient to induce cell death in ALL cells.
• Hyperactive Syk mimicked self-reactive BCR activation, engaging a negative selection mechanism.
• Patient-derived ALL cells express inhibitory receptors that calibrate oncogenic signaling.
• Pharmacological inhibition of INPP5D led to Syk hyperactivation and ALL cell death.

Conclusions:

• Targeted hyperactivation of Syk signaling is a viable strategy to eliminate ALL cells.
• This approach leverages the natural B-cell negative selection process.
• Inhibiting INPP5D offers a promising therapeutic avenue for overcoming drug resistance in human ALL.