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Chapter 10 Stem Cell Model of Hematologic Diseases 115

Early Late Immature Mature
HSC CLP Pro-B
Pre-B Pre-B B cell B cell

CD34
CD38
CD19
CD10
CD20

CD34+ CD34+ CD19+
CD19– CD19+ CD20+

B-ALL

Fig. 10.2 STAGES OF NORMAL EARLY B-CELL DIFFERENTIATION AND SCHEMATIC OF
LEUKEMIC STEM CELLS IN B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (B-ALL). Based on
several studies testing the ability of human B-ALL blasts to engraft in immunodeficient mice, it appears that
multiple blast populations in B-ALL are able to establish the disease in immunodeficient mice. For example,
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CD34 CD19 blasts as well as CD34 CD19 blasts from individual patients have been shown to be able to
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transplant leukemia in vivo and to give rise to CD34 and CD34 leukemic cells. Thus B-ALL does not appear
to follow a hierarchical model in which blasts with a more mature immunophenotype lose their stem cell
capacity as has been seen in some cases of acute myeloid leukemia.
progenitor cell phenotype. This begs the question whether P210 had different variable, joining and diversity segments (VDJ) rear-
BCR-ABL–positive ALL represents de novo ALL or CML in lym- rangement patterns compared to the prior CLL. The finding of
phoid blast crisis. aberrant HSCs in CLL suggest that they are primed to generate MBL
cells, which are likely to accumulate additional mutations that
eventually results in a clonal CLL disorder.
MATURE B-CELL MALIGNANCIES In a different approach, Damm et al investigated whether molecu-
lar alterations present in CLL cells could be traced to cells in the
The classification of mature B-cell malignancies based on their histol- earliest stages of hematopoietic development before committed B-cell
ogy and immunophenotypic resemblance to a particular stage of development. In fact, acquired mutations were detected in HSCs in
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lymphoid differentiation has led to the theory that each lymphoma the majority of the patients with CLL studied. These findings
subtype originates within lymphocytes at distinct differentiation support a preleukemic phase and the clinical implications imply that
stages (Fig. 10.3). Another model predicts that cells acquire initial treatments with true curative intent in CLL might require approaches
alterations at early stages, even at the HSC level, that may drive clonal other than those focused solely on cell-surface antigens restricted to
expansion or resistance to apoptosis and that these cells then develop B cells or B-cell receptor signaling pathways.
additional complementary alterations at a later stage that lead to overt
malignancy. Recent studies have identified novel lymphoid associated
mutations and alterations across large panels of lymphomas, creating HAIRY CELL LEUKEMIA
the opportunity to define the clonal architecture and cell-of-origin in
lymphoma subtypes. Hairy cell leukemia (HCL) is a chronic lymphoproliferative disorder
characterized as a mature B-cell malignancy based on the expression
of CD19, surface immunoglobulin, and the clonal rearrangement of
CHRONIC LYMPHOCYTIC LEUKEMIA immunoglobulin heavy and light chain genes. At the same time, HCL
cells also express cell surface markers not present on normal B cells,
Chronic lymphocytic leukemia (CLL) is a B-cell malignancy marked including CD103 and CD11c, which are typically expressed by
by the accumulation of clonal mature B cells in the lymph node, bone dendritic cells and monocytes. In addition, patients with HCL have
marrow, and/or blood. In nearly all cases, CLL is preceded by a long been known to have clinical features disparate from most mature
preleukemic monoclonal B cell lymphocytosis (MBL), though not all B-cell malignancies, including the absence of lymph node involve-
cases of MBL continue on to CLL. The precise cell within B-cell ment and frequent splenomegaly due to extramedullary hematopoiesis
development that gives rise to CLL has been debated for decades and (EMH). Recent identification of BRAFV600E mutations in nearly
two recent studies have implicated HSCs in the pathogenesis of CLL. 100% of patients with classic HCL provided genetic insight into the
Kikushige et al investigated the cellular origin of CLL by isolating pathogenesis of HCL and a clonal marker to track the origin and
distinct subpopulations of cells and assaying their ability to initiate propagation of HCL. The BRAFV600E mutation was found in
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disease in immunodeficient mice. Only the CD34 CD38 CD90 purified (Lin ) CD34 CD38 CD90 CD45RA HSCs in primary
fraction engrafted and this population, known to be highly enriched samples from patients with HCL. These aberrant HSCs were also
in HSCs, gave rise to both lymphoid and myeloid hematopoiesis. able to recapitulate BRAFV600E-mutant hematopoiesis after trans-
Interestingly, these engrafted mice showed an increased proportion plantation into NOD/SCID/gamma-null (NSG) mice. Additionally,
of polyclonal B cells and a population of monoclonal B cells express- conditional knock-in mice were generated expressing BRAFV600E
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ing CD5, akin to MBL. Further examination determined that they in either HSCs or CD19 cells. Those mice with BRAFV600E HSCs