Targeting survival pathways in chronic myeloid leukaemia stem cells

Abstract

leukaemia (CML) is a clonal myeloproliferative disorder characterized by the presence of a fusion oncogene BCR-ABL, which encodes a protein with constitutive TK activity. The implementation of tyrosine kinase inhibitors (TKIs) marked a major advance in CML therapy; however, there are problems with current treatment. For example, relapse occurs when these drugs are discontinued in the majority of patients who have achieved a complete molecular response on TKI and these agents are less effective in patients with mutations in the BCR-ABL kinase domain. Importantly, TKI can effectively target proliferating mature cells, but do not eradicate quiescent leukaemic stem cells (LSCs), therefore allowing disease persistence despite treatment. It is essential that alternative strategies are used to target the LSC population. BCR-ABL activation is responsible for the modulation of different signalling pathways, which allows the LSC fraction to evade cell death. Several pathways have been shown to be modulated by BCR-ABL, including PI3K/AKT/mTOR, JAK-STAT and autophagy signalling pathways. Targeting components of these survival pathways, alone or in combination with TKI, therefore represents an attractive potential therapeutic approach for targeting the LSC. However, many pathways are also active in normal stem cells. Therefore, potential targets must be validated to effectively eradicate CML stem cells while sparing normal counterparts. This review summarizes the main pathways modulated in CML stem cells, the recent developments and the use of novel drugs to target components in these pathways which may be used to target the LSC population. LINKED ARTICLES

Tyrosine kinase inhibition: a therapeutic target for the management of chronic-phase chronic myeloid leukemia

“…However, abolition of LSCs that give rise to disease persistence would be beneficial in the majority of patients and will most likely require an alternative, non-TKI approach to treatment. A number of intracellular signaling pathways and molecules have been identified that are potentially involved in LSC survival and these are being investigated as potential therapeutic targets [124,125]. The role of the bone marrow microenvironment in protecting LSCs is also under scrutiny [126,127].…”

Axl Blockade by BGB324 Inhibits BCR-ABL Tyrosine Kinase Inhibitor–Sensitive and -Resistant Chronic Myeloid Leukemia

“…Despite the dramatic clinical progress upon treatment with these drugs and the possibility to discontinue treatment in approximately 50% of patients (14), allogeneic stem cell transplantation represents the only proven long-term curative treatment (15)(16)(17). Therefore, novel therapeutic strategies are warranted to target persisting stem cells and resistant clones alone or in combination with BCR-ABL TKI.…”

The role of microenvironment and immunity in drug response in leukemia

“…Other pathways and mediators have been implicated in LSC/HSC survival, such as Akt phosphatidylinositol-3 kinase (PI3K) [20], NOTCH signalling [18], and the Wnt/β-catenin pathway [21]. It is possible to target these pathways, by inhibiting for example the activation of Akt using PI3K inhibitors.…”

“…It is possible to target these pathways, by inhibiting for example the activation of Akt using PI3K inhibitors. Sinclair and colleagues [21] provide a detailed overview of the various survival pathways in CML stem cells, in addition to discussing methods to target these pathways.…”