Recent therapeutic approaches to target the eradication of CP CML LSC. (A) Dual targeting of c-MYC and TP53 (p53) or combined treatment with TKI and EZH2 inhibitor (EZH2i).^98,100,101  Both approaches converge on upregulating p53-mediated apoptosis through different mechanisms. BETi and MDM2i lead to synergistic repression of c-MYC transcription and upregulation of p53 target genes. A dependency on EZH2 for LSC survival is accompanied by a TKI-independent downregulation of EZH1. (B) Inhibition of STAT5 upstream of the HIF2α-CITED2 pathway that governs LSC quiescence. Combining a PPARγ activator (PPARγa) with TKI^102,103  inhibits STAT5 transcription and STAT5 phosphorylation, respectively, and downregulates HIF2α-CITED2 leading to LSC exit from quiescence. (C) Inhibition of noncanonical Wnt/β-catenin signaling mediated by CD70/CD27. TKI upregulates the Wnt/β-catenin pathway by inhibiting miR-29 expression, facilitating both increased CD70 expression and CD70/CD27 receptor/ligand interaction. Treatment with a monoclonal antibody that blocks the CD70/CD27 interaction (αCD70) in a TKI background blocks the pathway.^66,67  (D) Activation of PP2A to inhibit a novel CML network driven by JAK2-β-catenin signaling. PP2A activating drugs (PADs) disrupt the PP2A-SET interaction, thereby allowing PP2A reactivation, which inhibits BCR-ABL1 recruitment of JAK2 (TKI-independent) and impairs β-catenin signaling through GSK-3β activation.⁷⁷  (E) Inhibition of ALOX15 to inhibit β-catenin and PI3K/AKT signaling. Knockdown of ALOX15 or treatment with a 15-LO inhibitor (15-LOi), which blocks ALOX15 enzymatic activity, reduced LSC survival in association with reduced PI3K/AKT and β-catenin levels. This “kill” phenotype was rescued by loss of p-selectin (SELP), which is thought to negatively regulate LSC self-renewal and survival.¹⁰⁶  Activation and repression are denoted according to convention. Drug treatments are shown in yellow. Further details are described in the text.