H e m a t o lo g y E d u c a t io n - European Hematology Association

M.T. Scott
A.M. McCaig
T.L. Holyoake
Paul O’Gorman Leukaemia
Research Centre, College of Medical,
Veterinary & Life Sciences, Institute
of Cancer Sciences, University
of Glasgow, Glasgow,
United Kingdom
MTS and AMM contributed equally
to this manuscript.
Hematology Education:
the education program for the
annual congress of the European
Hematology Association
2011;5:112-119
Chronic myeloid leukemia
Mechanisms of resistance in
chronic myeloid leukemia stem cells
Introduction
Over recent years, the historical view that
malignant tumors comprise a uniform population
of cells, each able to recapitulate the
neoplastic phenotype, has been challenged.
In many cancers, the existence of small populations
of tumor cells, which are refractory
to therapy, has long been appreciated, leading
to the cancer stem cell (CSC) hypothesis,
which proposes that tumors have a hierarchical
structure of differentiation akin to normal
tissues. 1 Only the CSCs have the ability
to self-renew and perpetuate the tumor, and
are therefore considered the source of disease
relapse. CSCs have been identified, and
at some level characterized in solid tumors,
including breast, brain, and prostate cancer. 1
In the hemopoietic system CSCs, referred to
as leukemic stem cells (LSCs), were first
demonstrated in acute myeloid leukemia
(AML) by Dick et al. in 1994, who isolated a
subpopulation of CD34+CD38- cells able to
induce AML on serial transplantation in
mice. 2 In this study, the LSCs comprised a
tiny fraction of the leukemic bulk, only
around 1 in 250,000 of the malignant cells.
LSC in chronic myeloid leukemia (CML)
were identified in 1999, 3 and this disease has
become a paradigm of the CSC hypothesis.
CML arises from a balanced translocation
between the long arms of chromosomes 9
and 22 within a hemopoietic stem cell
(HSC), which forms a constitutively active
tyrosine kinase, BCR-ABL1. 4 Moreover,
BCR-ABL1 expression within murine HSCs
consistently leads to a myeloproliferative
disorder in murine model systems. 5
CML is also credited as being at the forefront
of targeted cancer therapy, following
A B S T R A C T
Chronic myeloid leukemia (CML) has emerged as a paradigm for cancer stem cells (CSCs); including
leukemic stem cells (LSCs). Arising from a chromosomal translocation within an hemopoietic stem cell
(HSC), which generates the Philadelphia (Ph) chromosome, the resulting oncogenic protein, BCR-ABL1,
drives the disease. Targeted therapy against this constitutively active tyrosine kinase with tyrosine
kinase inhibitors (TKIs) has revolutionized the treatment of CML. While high rates of response have
been achieved, BCR-ABL1 gene transcripts can still be detected in the majority of patients, suggesting
residual disease. This disease persistence has been attributed to a small pool of drug-resistant CML
LSCs. Consequently, in recent years, the major focus of CML research has been to identify and target
the molecular mechanisms that confer drug-resistance on this LSC pool. In this review, we provide a
comprehensive overview of what is currently known about the mechanisms that mediate survival of
CML LSCs and the novel therapies emerging as a consequence to target these pathways.
the advent of imatinib mesylate, a smallmolecule
that inhibits BCR-ABL1 activity by
binding directly to the kinase domain. 6 Preclinical
studies demonstrated imatinib to
exert anti-proliferative and pro-apoptotic
effects on CML cells in vitro and in vivo, 6 supporting
the hypothesis that the malignant
cells in CML are kinase-addicted. The pivotal
phase III clinical trial of imatinib in CML, the
IRIS study, demonstrated imatinib to induce
complete cytogenetic response in just under
87% of patients. 7 Despite these promising
results, it is now appreciated that in most
patients, detectable levels of minimal residual
disease (MRD) persist on therapy, 7 and
molecular relapse is frequent on drug discontinuation.
8 Elegant mathematical models of
imatinib in CML demonstrate a biphasic
early response, with rapid elimination of differentiated
cells followed by slower depletion
of proliferating progenitors, but appear
unable to predict whether tyrosine kinase
inhibitors (TKIs) are likely to eliminate the
LSC compartment. 9,10 Fluorescence-activated
cell sorting (FACS) analysis of chronic phase
CML patient samples revealed that whilst
the majority of malignant stem cells were
actively recruited within the cell cycle, a subpopulation
of quiescent (G0) cells could be
consistently isolated. 3 Our laboratory has
shown that these quiescent BCR-ABL1+ve
stem cells are resistant to the apoptotic
effects of imatinib. 11 Moreover, we found the
TKI to exert an antiproliferative effect on the
quiescent LSC compartment, which may
further contribute to the persistence of
MRD. In support of this hypothesis, LSCs
have been shown to accumulate within the
bone marrow during TKI treatment in a
CML mouse model. 12 As LSCs are believed
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