Page 1465 - Williams Hematology ( PDFDrive )

1440 Part X: Malignant Myeloid Diseases Chapter 89: Chronic Myelogenous Leukemia and Related Disorders 1441

some patients. 47,49,54–63 Natural killer (NK) cells isolated from patients to differentiation and progenitor cell expansion is mediated by an auto-
with chronic phase CML do not contain the BCR-ABL1 fusion gene. crine interleukin (IL)-3–granulocyte colony-stimulating factor (G-CSF)
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It is possible that myelopoiesis is invariably clonal and lymphopoiesis loop. The earliest progenitors have the capacity to undergo marked
is an unpredictable mosaic derived largely from normal residual stem expansion of erythroid, granulocytic, and megakaryocytic cell pop-
cells. This conclusion is supported by the finding that progenitors of T, ulations, and have a decreased sensitivity to regulation. 105–107 This
B, and NK lymphocytes contain the Ph chromosome and BCR-ABL1, expansion is especially dramatic in the more mature progenitor cell
but most B-cell and all T-cell progenitors derived from the leukemic compartment. 105,108 The proliferative capacity of individual granulocytic
clone undergo apoptosis, leaving unaffected cells in the blood. 65–68 progenitors is decreased compared to normal cells. Thus, the progeni-
The cell in which the mutation occurs may be even more primitive tor cell population in marrow and blood expands proportionately more
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in that some endothelial cells generated in vitro express the BCR-ABL1 than the increase in granulopoiesis. BCR-ABL1 reduces growth factor
fusion gene, as do some cells in the patient’s vascular endothelium. 69 dependence of progenitor cells.
Erythroid progenitors are expanded, erythroid precursor matura-
ETIOLOGIC ROLE OF THE Ph CHROMOSOME tion is blocked at the basophilic erythroblast stage, and the extent of
Early studies indicated that the Ph chromosome may appear after the erythropoiesis is inversely proportional to the total white cell count. 110
initial leukemogenic event. 70–73 Patients with CML have developed the
Ph chromosome during the course of the disease, have experienced Progenitor Cell Characterization
periods of the disease when the Ph chromosome disappeared, or Phenotypic differences of stem and progenitor cells in CML patients
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have had Ph chromosome–positive and Ph chromosome–negative cells compared to normal subjects have been identified. For example, a
concurrently. 75–79 greater proportion of the circulating leukemic colony-forming unit–
Nearly all, if not all, patients with CML have an abnormality of granulocyte-monocytes (CFU-GMs) express high levels of the adhesion
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chromosome 22 at a molecular level (BCR rearrangement). Thus, earlier receptor CD44 and low levels of L-selectin in contrast to normal
studies indicating an absence of a Ph chromosome was not a valid mea- cells. Leukemic CD34+ cells overexpress the P glycoprotein that deter-
sure of the normality of chromosome 22. The molecular abnormality mines the multidrug resistance phenotype. 114
in CML involving the ABL1 gene on chromosome 9 and the BCR gene BCR-ABL1–positive progenitors survive less well in long-term cul-
on chromosome 22 has been established as being the proximate cause ture than do their normal counterparts. Leukemic CFU-GM colonies,
of the chronic phase of the disease (see “Molecular Pathology” below). unlike normal colonies, decrease in long-term cultures that are deficient
in KIT ligand, whereas their proliferation is favored in the presence
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COEXISTENCE OF NORMAL STEM CELLS of KIT ligand. Macrophage inflammatory protein (MIP)-1α, renamed
Most, if not all, patients with CML have hematopoietic stem cells CCL3, does not inhibit growth factor-mediated proliferation of CD34+
cells from CML patients, as it does CD34+ cells from normal subjects,
that, after treatment 80–82 or culture in vitro, 83–85 use of special cell iso- even though the CCL3 receptor is expressed. Another chemokine,
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lation techniques, 81,82 or use of cell transfer to nonobese diabetic monocyte chemotactic protein (MCP)-1 or CCL2, unlike CCL3, is
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(NOD)/severe combined immunodeficiency (SCID) mice do not an endogenous chemokine that cooperates with transforming growth
have the Ph chromosome 89,90 or the BCR-ABL1 fusion gene. 91–95 The factor beta (TGF-β) to inhibit the cycling of primitive normal, but not
switch to Ph chromosome–negative cells in vitro is associated with CML, progenitors in long-term human marrow cultures. Leukemic
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a loss of monoclonal glucose-6-phosphate dehydrogenase isoen- progenitors are less sensitive than normal progenitors to the antiprolif-
zyme patterns, indicating the persistence and reemergence of normal erative effects of TGF-β. 119
polyclonal hematopoiesis rather than reversion to a Ph chromosome–
negative clone. In confirmation, BCR-ABL1+, CD34+, human leu- Effects of BCR-ABL1 on Cell Adhesion
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kocyte antigen (HLA)-DR− cells isolated from women with early Primitive progenitors and blast colony-forming cells from patients with
phase CML are polyclonal using the human androgen receptor assay CML have decreased adherence to marrow stromal cells. This defect
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(HUMARA) to assess X chromosome inactivation patterns. Very is normalized if stromal cells are treated with interferon (IFN)-α. As
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primitive hematopoietic cells, the long-term culture–initiating cells a result, BCR-ABL1–negative progenitors are enriched in the adherent
(LTC-ICs), are present in Ph chromosome–negative cytapheresis sam- fraction of circulating CD34+ cells in chronic phase CML patients. The
ples collected during early recovery after chemotherapy for CML. most primitive BCR-ABL1–positive cells in the blood of patients with
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These LTC-ICs are most commonly present when samples are collected CML differ from their normal counterparts. They are increased in fre-
within 3 months of diagnosis. Variable levels of BCR-ABL1–negative quency and are activated, such that signals that block cell mitosis are
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progenitors are found in the CD34+DR− population, but low levels bypassed. 122
are found in the CD34+CD38− population. 95,100 Preprogenitors for the Ph chromosome–positive colony-forming cells adhere less to
CD34+DR− cells are predominantly BCR-ABL1–negative in both mar- fibronectin (and to marrow stroma) than do their normal counterparts.
row and blood at diagnosis. However, some cells with surface marker Adhesion is fostered as a result of restoration of cooperation between
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characteristics of very primitive normal hematopoietic cells do express activated β integrins and the altered epitopes of CD44. 123,124 CML
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the BCR-ABL1 gene. Both normal and leukemic SCID-repopulating granulocytes have reduced and altered binding to P-selectin because of
cells coexist in the marrow and blood from CML patients in chronic modification in the CD15 antigens. BCR-ABL1–induced defects in
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phase, whereas only leukemic SCID-repopulating cells are detected in integrin function may underlie the abnormal circulation and prolifera-
blast crisis. 103,104
tion of progenitors 126,127 because growth signaling can occur through the
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PROGENITOR CELL CHARACTERISTICS fibronectin receptor. IFN-α restores normal integrin-mediated inhi-
bition of hematopoietic progenitor proliferation by the marrow micro-
Progenitor Cell Dysfunction environment. There are conflicting data regarding the effects of TKI
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The leukemic transformation resulting from the BCR-ABL1 fusion effects on adhesion of CML cells to stroma. 130,131
oncogene is maintained by a relatively small number of BCR-ABL1 stem BCR-ABL1–encoded fusion protein p210 BCR-ABL binds to actin,
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cells that favor differentiation over self-renewal. This predisposition and several cytoskeletal proteins are thereby phosphorylated. The
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