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C H A P T E R 10

STEM CELL MODEL OF HEMATOLOGIC DISEASES

Justin Taylor and Omar Abdel-Wahab

CELL OF ORIGIN STUDIES IN HEMATOLOGIC aforementioned earliest studies of LICs in AML relied on their
transplantation into immunodeficient nonobese diabetic/severe
MALIGNANCIES combined immunodeficient (NOD/SCID) mice (see box on Evolu-
tion of Immunodeficient Mouse Models) to assay the ability of a
One of the prevailing models of cancer development proposes that a defined population of AML cells to give rise to AML in vivo. However,
cancer is initiated and maintained through the function of cancer using more immunodeficient xenotransplant models, primary human
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stem cells (CSCs), which represent a rare population of cells within cells from both CD34 CD38 and CD34 CD38 compartments
a cancer that have an indefinite proliferative potential and are ulti- have been shown to have LIC activity. In addition, work by Vyas and
mately responsible for the generation of the bulk of cancer cells. This colleagues has revealed that two expanded populations, both with
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so-called cancer stem cell hypothesis has been best studied in hema- LIC activity, exist in CD34 AML (Fig. 10.1). One population
topoietic malignancies. The ability to purify hematopoietic cells more shares the immunophenotype of normal LMPPs and the other
easily than cells from other tissues, combined with the well-defined mirrors the GMP population. The LMPP-like leukemic stem cell
cell-surface markers of hematopoietic cells, has allowed the prospec- (LSC) population can give rise to the GMP-like LSC population but
tive isolation of nearly every hematopoietic cell subset from humans either can give rise to AML in immunocompromised mice in vivo.
as well as mice. As described in the box on Functional Evaluation of Cell-of-
The CSC hypothesis proposes that cancers are organized into Origin In Vivo, the leukemogenic effects of specific oncogenes
hierarchical populations like normal tissues. At the apex of hierarchy directly depend on the specific oncogene as well as the target cell of
are largely quiescent long-lived CSCs with marked self-renewal capac- expression. Based on these facts, consistent LICs may be most easily
ity that sustain the disease and give rise to the majority of the bulk defined for specific genetically defined subsets of leukemias (such as
cancer cells that constitute the disease. While identification of a single specific chronic leukemias defined by specific translocations or point
normal hematopoietic cell subset as the target of the malignant mutations) but are much more difficult to define for normal karyo-
transformation and the cellular reservoir for disease has been possible type AML. For example, expression of the AML1-ETO fusion tran-
for a variety of myeloid leukemias and lymphomas, pinpointing a script, generated by the common t(8;21) translocation in AML, can
single cell as the target of malignant transformation has not yet be detected not only in leukemic cells but also in normal HSCs from
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proven possible for other hematopoietic malignancies. In this chapter, patients in clinical remission from AML. However, these AML1-
we will discuss efforts to identify the malignant stem cell for each of ETO–expressing HSCs are not leukemic and can differentiate into
the common forms of myeloid and lymphoid leukemias. myeloid and erythroid cells in vitro in a manner similar to HSCs
without the AML1-ETO fusion transcripts (Fig. 10.1). Similarly,
analysis of mice expressing the AML1-ETO fusion from the endog-
ACUTE MYELOID LEUKEMIA enous Aml1 locus in vivo has revealed that AML1-ETO–expressing
HSCs have aberrant self-renewal capacity but do not develop overt
The first evidence of a stem cell origin of malignancy came from leukemia unless additional genetic abnormalities are present. These
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studies in 1997 performed by Blair et al as well as Bonnet and Dick data strongly suggest that acquisition of additional genetic abnormali-
into acute myeloid leukemia (AML). These studies demonstrated that ties in a subset of HSCs or their progeny is required to give rise to
most leukemia cells were unable to proliferate extensively and that overt leukemia. In these studies the HSCs bearing the AML1-ETO
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only a subset of cells was consistently clonogenic. In these studies a fusion reside within the Lin CD34 CD38 subpopulation that is also
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small subset of human Thy1 CD34 CD38 AML cells (0.2–1.0%) the immunophenotype of normal human HSCs, suggesting that the
was identified and shown to be the only cells capable of transferring initiating lesion must occur in a cell with an immunophenotype of
human AML to immunodeficient mice. In humans, normal hema- normal HSCs. However, leukemic cells from 30% to 40% of patients
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topoietic stem cells (HSCs) reside in the lineage-negative (Lin ) with AML do not express CD34, and LICs from some patients with
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CD34 CD38 CD90 CD45RA compartment and generate multi- AML can actually be CD34 . Interestingly, prior work evaluating the
potent progenitors with lymphomyeloid potential (LMPPs) defined location of the PML-RARA transcript present in acute promyelocytic
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as Lin CD34 CD38 CD90 CD45RA cells, as well as more commit- leukemia (APL) revealed that the PML-RARA translocation is actu-
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ted myeloid progenitors that are present in the CD34 CD38 com- ally present in CD34 CD38 populations and not in CD34 CD38
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partment. Among the myeloid progenitors, the common myeloid HSC-enriched populations (Fig. 10.1). These data clearly reveal that
progenitors (CMPs), granulocyte–macrophage progenitors (GMPs), there is enormous heterogeneity in the cell-of-origin of AML.
and megakaryocyte-erythroid progenitors (MEPs) can be discrimi- Advancement in techniques to map genetic alterations in cancer
nated based on differential expression of CD123 (IL3RA), CD110 have allowed for much finer tracking of somatic mutations in AML
(MPL), and CD45RA. and other hematopoietic malignancies with a normal karyotype. It is
The initial observation that AML leukemia-initiating cells (LICs) now believed that an average of five coding mutations is present in
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reside within the CD34 CD38 compartment suggested that AML adults with de novo AML. Several groups have now studied the
HSCs are rare cells that most closely resemble normal HSCs sharing occurrence of somatic mutations in bulk AML cells and the remain-
a common limited immunophenotype and being in rare populations ing seemingly nonaffected HSCs. This work has clearly shown that
(Fig. 10.1). However, subsequent data have suggested that this con- the HSC compartment in patients with AML contains HSCs with
clusion is an oversimplification and that the cell of origin of any none of the mutations found in the AML as well as HSCs with
myeloid malignancy is likely dictated by a combination of the specific various combinations of genetic alterations similar to that present in
genetic and epigenetic alterations present in the individual patient as the bulk malignant cells (Fig. 10.1). These latter HSCs are now
well as the cells in which these alterations occur. For example, the understood to be “preleukemic stem cells” that initiate AML and can
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