hematology education - European Hematology Association

M.W. Deininger
Oregon Health & Science University,
Portland, OR, USA
Hematology Education:
the education program for the
annual congress of the European
Hematology Association
2009;3:72-77
Chronic myeloid leukemia
Stem cell persistence in chronic myeloid leukemia
Clinical and molecular features of chronic
myeloid leukemia
Chronic myeloid leukemia (CML) is characterized
by a 2-phase clinical course. In the
developed world, most patients are diagnosed
in the chronic phase, which is characterized
by grossly increased output of
myeloid cells, whose differentiation and
function is largely maintained. 1 Historical
data suggest that the median duration of the
chronic phase, in the absence of any effective
therapy, is 2-3 years, after which there is
a progressive loss of cellular differentiation
that culminates in the blastic phase, an acute
leukemia of myeloid or lymphoid phenotype.
While complications in the chronic
phase are rare, blast crisis is a rapidly fatal
disease. Thus, the foremost aim of CML
therapy is to prevent the progression from
the chronic to the blastic phase.
The cytogenetic hallmark of CML is the
Philadelphia chromosome (Ph), the consequence
of the t(9;22)(q34;q11). At the molecular
level, the translocation leads to the
fusion of BCR genetic sequences upstream
of the ABL gene on chromosome 9. The
resulting BCR-ABL fusion protein is that
activates multiple signaling pathways,
including mitogen activated protein kinases
(MAPK), phosphotidyl inositol 3’ kinase
(PI3K) and Janus kinase/signal transduction
and activation of transcription (JAK/STAT)
signaling, amongst many others.
Collectively, these pathways increase proliferation,
inhibit apoptosis, induce genetic
instability and perturb the interaction
between the CML cells and their microenvironment.
The identification of non-redundant
components in this complex signaling
network has proved difficult, consistent
with a high degree of redundancy. However,
it is clear that the tyrosine kinase activity of
BCR-ABL is conditio sine qua non of leukemogenesis.
2
It has been a matter of debate whether
BCR-ABL is sufficient to induce the chronic
phase of CML. Early studies based on glucose
6 phosphate dehydrogenase (G6PD)
isoenzyme expression in EBV-transformed
Ph-negative B cell lines from CML patients
had suggested that a clonal state predates
the acquisition of Ph. 3-4 Over the years, substantial
evidence has accumulated in support
of the notion that chronic phase CML does
not require mutations in addition to Ph.
Thus, chromosomal abnormalities in Ph-
positive cells, referred to as clonal evolution,
are rare in newly diagnosed chronic phase
patients. 5 Moreover, polyclonal hematopoiesis
is restored in most patients with a
complete cytogenetic response (CCyR) to
imatinib. 6 Lastly, bone marrow infected with
BCR-ABL retrovirus causes a polyclonal
CML-like myeloproliferative disease upon
transplantation into lethally irradiated syngeneic
recipients, consistent with a single hit
pathogenesis. 7 What these data cannot
exclude is that in human CML, a mutation
may be acquired before BCR-ABL, but without
causing clonal expansion. This notion
has attracted renewed interest from observations
in Ph-negative JAK2 V617F -positive MPD,
where acute leukemia may arise from
JAK2 WT cells, consistent with a JAK2 V617F -negative
abnormal cell at increased risk of transformation
to acute leukemia. 8 Moreover, the
clinical course of newly diagnosed patients
with seemingly exchangeable disease presentations
can be very different, indicating a
level of disease heterogeneity that is not
appreciated by the resolution of morphology
and cytogenetics. 9
Cell of origin
Studies using infection of immunophenotypically
and functionally defined murine
hematopoietic progenitor and stem cells have
revealed that BCR-ABL does not confer self
renewal capacity to progenitor cells, unlike
AML-related fusion genes, such as MOZ-
TIF2. 10 This implies that the BCR-ABL translocation
must be acquired by a hematopoietic
stem cell that is able to self-renew. In support
of this, BCR-ABL has been demonstrated in all
hematopoietic lineages and in lineage-negative
CD34 + /CD38 – cells. 11-12 For mechanisms
that are not well understood, cellular expansion
is, however, limited to the myeloid
compartment, particularly granulocytes and
their precursors. Interestingly, the degree to
which the “stem cell” compartment is penetrated
by the BCR-ABL-positive cell clone is
extremely variable. 12 Although precise data
are unavailable, it is believed that a more
complete replacement of the stem cell compartment
with leukemic cells is a feature of
long-standing disease. From a clinical view,
the paucity of residual normal cells present
in the marrow of patients with CML of
many years’ duration may be responsible for
the frequent cytopenias of such patients on
imatinib therapy. From the fact that CML
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