JAK2 and chronic myelogenous leukemia, BCR-ABL1 positive: CML LSCs are able to maintain self-renewal and survival through multiple mechanisms of resistance to TKI-mediated BCR-ABL1 inhibition, encompassing cell signaling (e.g., WNT, SHH, and TGFβ) with activation of kinases (e.g., PI3K/AKT, RAS/MEK/ERK, and JAK2/STAT3/5) leading to transcriptional activation through epigenetic and transcriptional regulation (Fig. 2).