Chronic Myelogenous Leukemia — Identifying the Hydra's Heads
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《新英格兰医药杂志》
Chronic myelogenous leukemia (CML) begins as an indolent disease in which the myeloid lineages in the bone marrow and blood gradually expand. Untreated, this chronic phase of CML inexorably progresses to an accelerated phase and finally to a blast crisis, in which large numbers of blast cells appear in the bone marrow and blood. The hallmark of CML is the Philadelphia chromosome, which corresponds to a t(9;22) translocation in which sequences of BCR that encode the N-terminal region of the BCR protein fuse with the tyrosine kinase catalytic domain of the ABL oncogene. This chimeric gene (BCR-ABL) is central to the development of CML, but additional mutations are involved, especially during the evolution of the chronic phase into the blast crisis.
Treatment of CML becomes progressively more difficult as the disease advances. Allogeneic bone marrow transplantation can cure chronic-phase CML in up to 70 percent of patients, but the use of this procedure is limited by the toxicity of the treatment, the risk of graft-versus-host disease, and the lack of suitable donors for many patients. Up to 60 percent of patients with chronic-phase CML enter a period of remission when treated with imatinib, an inhibitor of the BCR-ABL kinase. Despite its remarkable efficacy, imatinib may not be curative, because early progenitor cells carrying the Philadelphia chromosome persist in most patients, despite treatment. Just as the Hydra regenerated two heads for each one that was severed, the blasts in most patients with blast crisis rapidly regenerate after initially regressing in response to imatinib.
Like virtually all cancers, CML arises in a tissue with short-lived mature cells that are constantly being replaced by a small population of stem cells. In normal bone marrow, hematopoietic stem cells give rise to progressively more highly differentiated progenitor cells, which eventually differentiate into mature blood cells (see Figure). A unique property distinguishes stem cells from progenitor cells: they have the ability to divide and form one new stem cell (a process called self-renewal) and one daughter cell with the capacity to differentiate into mature blood cells. Both daughters of a progenitor cell, by contrast, become progressively more highly differentiated and lose proliferative capacity at each cell division. Genetic studies of women with CML who were heterozygous for the X-linked glucose-6-phosphate dehydrogenase gene (G6PD) or for other X-linked genes demonstrated clonal, multilineage hematopoiesis in which mature blood cells were derived from cells with the Philadelphia chromosome. These observations led to the understanding that only a subgroup of leukemia cells share with normal hematopoietic stem cells the capacity for self-renewal and that these CML stem cells drive the disease.
Figure. Cellular Hierarchy in Normal Hematopoiesis and in CML.
Proposed cell compartments in normal hematopoiesis (Panel A), chronic-phase CML (Panel B), and CML blast crisis (Panel C) are shown. The circular arrows represent self-renewing compartments that contain cells with nuclear -catenin. Secondary events involving ongoing mutations leading to progression to blast crisis could occur in CML stem cells, granulocyte–macrophage precursors, or both. Ph1 denotes the Philadelphia chromosome.
Until now, the characteristics of self-renewing leukemic cells in CML have been unknown. In this issue of the Journal, Jamieson and colleagues (pages 657–667) report the identification of self-renewing leukemic stem cells in the chronic phase of CML and in CML blast crisis. Their finding is surprising and has important implications for the treatment of the disease. Earlier work from these investigators showed that -catenin can drive self-renewal in stem cells and that nuclear localization of this protein in blood cells is limited to hematopoietic stem cells.1 They now report that in the chronic phase of CML, progenitor-cell populations expand, but the size of the leukemic stem-cell compartment, where cells harboring the Philadelphia chromosome contain exclusively nuclear -catenin, is normal (see Figure). This finding suggests that although leukemic stem cells in CML express BCR-ABL, the mutant protein affects a more critical function in progenitor cells than it does in leukemic cells. If so, treatment that targets the BCR-ABL protein would primarily affect leukemic progenitor cells while sparing self-renewing leukemic stem cells. Such a differential effect could explain the persistence of primitive cells with the Philadelphia chromosome in most patients with CML, despite treatment with imatinib.
Jamieson et al. also determined the self-renewal capacity of various populations of blood cells in the blast crisis. Surprisingly, granulocyte–macrophage progenitors from patients with CML in blast crisis were found to have self-renewal capabilities and to accumulate nuclear -catenin. These findings indicate that there are two populations of self-renewing cells in CML: classic CML stem cells and blast-crisis granulocyte–macrophage progenitors (see Figure). These findings have important implications for the treatment of CML. Most treatments for blast crisis are chosen for their ability to eliminate blasts from the bone marrow. However, since self-renewing blast-crisis progenitors appear to underlie the crisis, these progenitors — like a Hydra with a severed head — continue to replenish the population of blasts in the marrow because the treatment is not directed against them.
The existence of a definable, self-renewing population of granulocyte–macrophage progenitors of blast crisis suggests strategies for the development of new treatments for CML. The -catenin pathway of self-renewal is a possible target, even though both normal stem cells and granulocyte–macrophage blast-crisis progenitors use this mechanism to renew themselves. If normal granulocyte–macrophage progenitors are also eliminated as part of treatment, there would be little consequence, since they would be replaced by residual normal hematopoietic stem cells. An important unanswered question is whether both leukemic stem cells and blast-crisis progenitors in CML also harbor the mutations that lead to blast crisis. If so, treatments that specifically target blast-crisis progenitors might spare self-renewing leukemic stem cells, making relapse inevitable. Nonetheless, leukemic stem cells, normal stem cells, and leukemic progenitors might use critical pathways that differ with respect to the way in which -catenin is activated. Such differences could be exploited to eliminate self-renewing leukemic cells selectively.
Source Information
From the Departments of Medicine and Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor.
References
Reya T, Duncan AW, Ailles L, et al. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature 2003;423:409-414.(Michael F. Clarke, M.D.)
Treatment of CML becomes progressively more difficult as the disease advances. Allogeneic bone marrow transplantation can cure chronic-phase CML in up to 70 percent of patients, but the use of this procedure is limited by the toxicity of the treatment, the risk of graft-versus-host disease, and the lack of suitable donors for many patients. Up to 60 percent of patients with chronic-phase CML enter a period of remission when treated with imatinib, an inhibitor of the BCR-ABL kinase. Despite its remarkable efficacy, imatinib may not be curative, because early progenitor cells carrying the Philadelphia chromosome persist in most patients, despite treatment. Just as the Hydra regenerated two heads for each one that was severed, the blasts in most patients with blast crisis rapidly regenerate after initially regressing in response to imatinib.
Like virtually all cancers, CML arises in a tissue with short-lived mature cells that are constantly being replaced by a small population of stem cells. In normal bone marrow, hematopoietic stem cells give rise to progressively more highly differentiated progenitor cells, which eventually differentiate into mature blood cells (see Figure). A unique property distinguishes stem cells from progenitor cells: they have the ability to divide and form one new stem cell (a process called self-renewal) and one daughter cell with the capacity to differentiate into mature blood cells. Both daughters of a progenitor cell, by contrast, become progressively more highly differentiated and lose proliferative capacity at each cell division. Genetic studies of women with CML who were heterozygous for the X-linked glucose-6-phosphate dehydrogenase gene (G6PD) or for other X-linked genes demonstrated clonal, multilineage hematopoiesis in which mature blood cells were derived from cells with the Philadelphia chromosome. These observations led to the understanding that only a subgroup of leukemia cells share with normal hematopoietic stem cells the capacity for self-renewal and that these CML stem cells drive the disease.
Figure. Cellular Hierarchy in Normal Hematopoiesis and in CML.
Proposed cell compartments in normal hematopoiesis (Panel A), chronic-phase CML (Panel B), and CML blast crisis (Panel C) are shown. The circular arrows represent self-renewing compartments that contain cells with nuclear -catenin. Secondary events involving ongoing mutations leading to progression to blast crisis could occur in CML stem cells, granulocyte–macrophage precursors, or both. Ph1 denotes the Philadelphia chromosome.
Until now, the characteristics of self-renewing leukemic cells in CML have been unknown. In this issue of the Journal, Jamieson and colleagues (pages 657–667) report the identification of self-renewing leukemic stem cells in the chronic phase of CML and in CML blast crisis. Their finding is surprising and has important implications for the treatment of the disease. Earlier work from these investigators showed that -catenin can drive self-renewal in stem cells and that nuclear localization of this protein in blood cells is limited to hematopoietic stem cells.1 They now report that in the chronic phase of CML, progenitor-cell populations expand, but the size of the leukemic stem-cell compartment, where cells harboring the Philadelphia chromosome contain exclusively nuclear -catenin, is normal (see Figure). This finding suggests that although leukemic stem cells in CML express BCR-ABL, the mutant protein affects a more critical function in progenitor cells than it does in leukemic cells. If so, treatment that targets the BCR-ABL protein would primarily affect leukemic progenitor cells while sparing self-renewing leukemic stem cells. Such a differential effect could explain the persistence of primitive cells with the Philadelphia chromosome in most patients with CML, despite treatment with imatinib.
Jamieson et al. also determined the self-renewal capacity of various populations of blood cells in the blast crisis. Surprisingly, granulocyte–macrophage progenitors from patients with CML in blast crisis were found to have self-renewal capabilities and to accumulate nuclear -catenin. These findings indicate that there are two populations of self-renewing cells in CML: classic CML stem cells and blast-crisis granulocyte–macrophage progenitors (see Figure). These findings have important implications for the treatment of CML. Most treatments for blast crisis are chosen for their ability to eliminate blasts from the bone marrow. However, since self-renewing blast-crisis progenitors appear to underlie the crisis, these progenitors — like a Hydra with a severed head — continue to replenish the population of blasts in the marrow because the treatment is not directed against them.
The existence of a definable, self-renewing population of granulocyte–macrophage progenitors of blast crisis suggests strategies for the development of new treatments for CML. The -catenin pathway of self-renewal is a possible target, even though both normal stem cells and granulocyte–macrophage blast-crisis progenitors use this mechanism to renew themselves. If normal granulocyte–macrophage progenitors are also eliminated as part of treatment, there would be little consequence, since they would be replaced by residual normal hematopoietic stem cells. An important unanswered question is whether both leukemic stem cells and blast-crisis progenitors in CML also harbor the mutations that lead to blast crisis. If so, treatments that specifically target blast-crisis progenitors might spare self-renewing leukemic stem cells, making relapse inevitable. Nonetheless, leukemic stem cells, normal stem cells, and leukemic progenitors might use critical pathways that differ with respect to the way in which -catenin is activated. Such differences could be exploited to eliminate self-renewing leukemic cells selectively.
Source Information
From the Departments of Medicine and Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor.
References
Reya T, Duncan AW, Ailles L, et al. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature 2003;423:409-414.(Michael F. Clarke, M.D.)