PLCG1 confers dependence in AE-driven leukemia. Expression of the AE fusion protein leads to upregulation of PLCG1, which is normally maintained in autoinhibited state. Activation of receptor or nonreceptor tyrosine kinases phosphorylates tyrosine 783 of PLCG1 activates its enzymatic activity. Activated PLCG1 hydrolyzes PIP2 to membrane-bound DAG and cytosolic IP3. Elevated IP3 activates calcium channel in the endoplasmic reticulum, leading to a cytosolic surge of calcium, which causes activation of calmodulin-calcineurin and NFATc activation. In parallel, DAG-mediated signaling leads to activation of NF-κB and AP1 transcription factor. Future studies will determine whether activation of NFATc is sufficient for AE-induced leukemogenesis and to what extent AP1 and NF-κB function is needed to support disease progression.