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Chapter 10 Stem Cell Model of Hematologic Diseases 117

showed an HCL-like phenotype of anemia, thrombocytopenia, and recipient had received a donor-lymphocyte infusion (DLI) 7 years
EMH; however, no phenotypic hairy cells were seen. In contrast, prior, which also harbored the same BCL-2/IGH and VDJ rearrange-
mice with BRAFV600E expression limited to lineage committed B ments, thus confirming the donor-derived source. There was no
cells did not have reduced survival or an overt phenotype. These data sample left of the original stem cell transplant to test but the BCL-2/
+
suggest that HCL is initiated within the HSC compartment but that IGH rearrangement was not present in the cells other than CD19
the development of additional genetic alterations occurring along the mature B cells in the DLI sample. However, there were mutations
−
+
−
course of hematopoiesis may be necessary to give rise to HCL cells. known to occur in lymphoma present in the CD34 CD10 CD19
30
Indeed, in patients with genetic alterations in addition to BRAFV600E population that includes multipotent progenitors and HSCs. These
in HCL cells, these additional mutations were not found in the alterations presumably contributed to the development of FL prior
BRAF-mutated HSCs. 27 to the acquisition of the hallmark translocation and occur in progeni-
tors of the follicle B cell. These findings provide evidence of a possible
role of stem cell progenitors in the development of mature B-cell
DIFFUSE LARGE B-CELL LYMPHOMA malignancies.
High-resolution genomic analyses of a large number of human diffuse
large B-cell lymphoma (DLBCL) samples identified copy number gain CONCLUSION
of chromosome 3q27.2 to be associated with the worst prognosis and
the aggressive activated B-cell (ABC) disease subtype. The transcrip- The stem cell model of hematologic diseases has implications beyond
tion factor BCL6 is likely the target oncogene affected by this copy a theoretical construct for the pathogenesis of disease. Not only does
number alteration at this locus given its propensity to be targeted by this model support stem cell transplant and gene therapy as curative
other alterations in DLBCL such as translocations and point muta- treatments in some cases, but also has much broader application in
tions, which were mutually exclusive from the 3q27.2 gain. Other the management of hematologic malignancies. Most of our current
roles for BCL6 have been described in normal hematopoiesis and standard therapies are based on the principle of interrupting DNA
myeloid leukemia stem cells, prompting inquiries into whether BCL6 replication in rapidly dividing cancer cells, yet stem cells are quiescent
expression in HSCs has a role in the origins of DLBCL. This hypoth- and spend little time in active cell cycle. Many of the new and
esis was tested by the generation of a mouse model that expressed developing therapies are targeted at cell surface markers or mutated
BCL6 only in HSCs, under the control of a stem cell–specific promo- genes whose expression may be restricted to the most mature malig-
tor so that BCL6 was no longer expressed by the differentiated nant cells and may be lacking in the premalignant or malignant stem
progeny. These mice developed a form of lymphoma that resembled cells. It remains to be seen whether the same challenges will face
28
DLBCL with an ABC phenotype that did not overexpress BCL6. immune response checkpoint modulators, but one could consider the
This led to a proposed model of “hit-and-run” oncogenesis, wherein possibility that neoepitopes recognized by activated T cells might
BCL6 expression in hematopoietic precursors is sufficient to produce have differential expression on different cell populations.
DLBCL without requiring sustained overexpression. Remarkable progress has been made in the field of CSCs in
hematologic malignancies due to the evolution of immunodeficient
mouse models and the improvement of sequencing technologies that
FOLLICULAR LYMPHOMA have allowed the mapping of clonal evolution and studies of muta-
tional ontogeny. There are controversies from inside and outside of
The most common subtype of lymphoma is follicular lymphoma the field as to whether stem cells should be defined phenotypically,
(FL), which is so named because histologically the lymph node fol- molecularly, or functionally but as the evidence accumulates there is
licle B cell is affected. These aberrant B cells carry a hallmark trans- broad agreement on the stem cell model of hematologic diseases.
location between chromosomes 14 and 18, resulting in juxtaposition
of the immunoglobulin heavy chain gene (IGH) and the antiapop-
totic protein BCL-2, thus driving overexpression of BCL2 and REFERENCES
resistance to programmed cell death. This malignancy usually follows
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toms of malignancy but are not currently subjected to genetic testing cells in a humanized mouse model. Nat Biotechnol 32:364–372, 2014.
for premalignant conditions. Often the donor is a brother or sister 7. Cosgun KN, et al: Kit regulates HSC engraftment across the human-
due to the 25% chance of being a complete HLA-match and the mouse species barrier. Cell Stem Cell 15:227–238, 2014.
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the recipient after stem cell transplantation. In the case mentioned are PML-RARA negative and generate nonclonal progenitors in acute
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