Chronic myeloid leukemia stem cells

Abstract

Chronic myeloid leukemia (CML) is caused by BCRABL1 in a cell with the biological potential, intrinsic or acquired, to cause leukemia. This cell is commonly termed the CML leukemia stem cell (LSC). In humans a CML LSC is operationally-defined by ≥1 in vitro or in vivo assays of human leukemia cells transferred to immune-deficient mice. Results of these assays are sometimes discordant. There is also the unproved assumption that biological features of a CML LSC are stable. These considerations make accurate and precise identification of a CML LSC difficult or impossible. In this review, we consider biological features of CML LSCs defined by these assays. We also consider whether CML LSCs are susceptible to targeting by tyrosine kinase inhibitors (TKIs) and other drugs, and whether elimination of CML LSCs is needed to achieve therapy-free remission or cure CML.

Fig. 1

Structural and functional features of the bone marrow microenvironment. Before TKI-therapy downregulation of CXCR4 by P210^BCRABL1 and increased expression of CD26 on CML LSCs causes them to exit the bone marrow and enter the blood. TKI-therapy reverses these effects causing CML LSCs are home to the bone marrow promoting their persistence

Fig. 2

Possible signaling pathways in CML LSCs. Binding of WNT to the frizzled receptor and LRP as co-receptor and activation of WNT/β-catenin is considered the normal signaling mechanism. However, stabilization and transduction of β-catenin into nucleus by P210^BCRABL1 and stimulation of CD70-CD27 after TKI-therapy may be specific to CML LSCs. Activation of WNT/Ca²⁺/NFAT favors CML LSC resistance to imatinib. Attachment of Hedgehog signaling ligands to the Ptch receptor activates Gli family transcription factors. Induction of PI3K activity by P210^BCRABL1 phosphorylates PIP2 resulting in recruitment of PDK1 which phosphorylates AKT activating mTORC1 and sequesters FOXO transcription factors. TKI-therapy enhances nucleus localization of FOXOs increasing survival of CML LSCs. Activation of JAK/STAT signaling by P210^BCRABL1 also increases survival of CML LSCs

Fig. 3

Autophagy in CML. The interaction of P210^BCRABL1 with PI3K-AKT inhibits autophagy. Contrariwise, TKIs inhibit kinase activity of P210^BCRABL1 enhancing autophagy. These autophagy effects may kill CML progenitor cells but may preserve CML LSCs

Fig. 4

Potential molecules and pathways to target CML LSCs