Table 1.

Resistance of CML stem cells against imatinib: Proposed hypotheses^*

Observations	Specific hypothesis/ molecular basis
Stem cell quiescence (dormance)	G0 arrest by chalones or by specific cell cycle regulators, quite similar mechanisms may lead to dormance of normal stem cells**
Stem cell plasticity	Development of subclones may be facilitated by mechanisms similar to those responsible for differentiation of normal myeloid stem cells into various myeloid lineages** – exact mechanisms are unknown
Overexpression of BCR/ABL	BCR/ABL mRNA and protein over- expression – mechanisms unknown
Specific BCR/ABL-induced stem cell deregulation	Altered DNA repair; hypermethylation; induction of stem cell subclones. Over time, BCR/ABL may overcome some of the stem cell-protecting mechanisms
BCR/ABL-independent survival	Stem cell-specific survival factors; altered survival factors in subclones***
Decreased uptake of imatinib	Decreased expression of OCT-1, a major transporter of imatinib
Increased drug efflux	Overexpression of P-glycoprotein(MDR-1) and other efflux pumps****

Notes:

^*Relate all to differences between CML stem cells and more mature CML cells. The following articles refer to these concepts: Copland et al 2005, ²⁰⁰⁶; Barnes and Melo 2006; Brendel et al 2007; Jiang et al 2007b);

^**The biology of normal stem cells and CML stem cells may be quite similar;

^***CML stem cells may even survive after complete deactivation of BCR/ABL;

^****Normal and neoplastic stem cells may defend their long-term existence against external ‘enemies’ (toxins, drugs) by high toxin/drug efflux.

Abbreviations: OCT-1, organic cation transporter; MDR-1, multidrug resistance gene-1.