Acute Myeloid Leukemia
المؤلف:
Hoffman, R., Benz, E. J., Silberstein, L. E., Heslop, H., Weitz, J., & Salama, M. E.
المصدر:
Hematology : Basic Principles and Practice
الجزء والصفحة:
8th E , P149-150
2025-10-23
35
The first evidence of a stem cell origin of malignancy came from studies in 1997 performed by Blair et al., as well as Bonnet and Dick in acute myeloid leukemia (AML). These studies demonstrated that most leukemia cells were unable to proliferate extensively and that only a subset of cells was consistently clonogenic. In these studies, a small subset of human Thy1−CD34+CD38− AML cells (0.2% to 1.0%) was identified and shown to be the only cells capable of transferring human AML to immunodeficient mice. In humans, normal hematopoietic stem cells (HSCs) reside in the lineage-negative (Lin−) CD34+CD38−CD90+CD45RA− compartment and generate multi potent progenitors with lymphomyeloid potential (LMPPs) defined as Lin−CD34+CD38−CD90−CD45RA− cells, as well as more com mitted myeloid progenitors that are present in the CD34+CD38+ compartment . Among the myeloid progenitors, the common myeloid progenitors (CMPs), granulocyte-macrophage pro genitors (GMPs), and megakaryocyte-erythroid progenitors (MEPs) can be discriminated based on the differential expressions of CD123 (IL3RA), CD110 (MPL), and CD45RA.
The initial observation that AML leukemia-initiating cells (LICs) reside within the CD34+CD38− compartment suggested that AML HSCs are rare cells that most closely resemble normal HSCs, sharing a common limited immunophenotype and being a rare population (Fig. 1). However, subsequent data have suggested that this conclusion is an oversimplification and that the cell of origin of any myeloid malignancy is likely dictated by a combination of the specific genetic and epigenetic alterations present in the individual patient as well as the cells in which these alterations occur. For example, the aforementioned earliest studies of LICs in AML relied on their transplantation into immunodeficient nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice (see box on Evolution of Immunodeficient Mouse Models) to assay the ability of a defined population of AML cells to give rise to AML in vivo. However, using more immunodeficient xenotransplant models, primary human cells from both CD34+CD38− and CD34+CD38+ compartments have been shown to have LIC activity. In addition, work by Vyas and col leagues has revealed that two expanded populations, both with LIC activity, exist in CD34+ AML (see Fig. 1). One population shares the immunophenotype of normal LMPPs and the other mirrors the GMP population. The LMPP-like leukemic stem cell (LSC) population can give rise to the GMP-like LSC population, but either can give rise to AML in immunocompromised mice in vivo.
Fig1. SCHEMATIC MODELS DEPICTING THE ORIGIN OF LEUKEMIC STEM CELLS (LSCS) IN VARIOUS MYELOID MALIGNANCIES. (A) Genetic evidence from some forms of acute and chronic myeloid leukemias reveals that the inciting genetic event occurs in a cell type in which normal hematopoietic stem cells (HSCs) are enriched (lineage-negative (Lin−)CD34+CD38−). For example, the AML1-ETO and BCR-ABL translocations found in acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) are present in HSCs. In addition, the JAK2V617F mutation is present in HSCs. However, the presence of these mutations alone may not be sufficient to generate overt AML and may be associated with aberrant self-renewal (as is the case with AML1-ETO) or chronic myeloproliferation (as with BCR-ABL and JAK2V617F) alone. (B) In contrast, other forms of AML appear to be generated due to the acquisition of genetic alterations in a cell type more differentiated than HSCs. For example, PML-RARA translocations occur in Lin−CD34+CD38+ cells in patients with acute promyelocytic leukemia (APL). (C) In addition, in a proportion of patients with de novo non-APL AML, LSC activity may be present in a cell with an immunophenotype distinct from HSCs. In some cases, multiple populations of LSCs may be present, each with a distinct immunophenotype as shown. (D) Finally, most recently, it has been proposed that genetic alterations may occur in a proportion of HSCs in patients with AML and that confer aberrant self-renewal properties to these cells. Further stepwise accumulation of genetic alterations then occurs in these preleukemic HSCs results in an overt malignant phenotype. As shown, mutations associated with the preleukemic HSCs include genes affecting DNA methylation and chromatin state, whereas mutations associated with frank leukemia include genetic alterations associated with increased cell proliferation.
As described in the box on Functional Evaluation of Cell-of Origin In Vivo, the leukemogenic effects of specific oncogenes directly depend on the specific oncogene as well as the target cell of expression. Based on these facts, consistent LICs may be most easily defined for specific genetically defined subsets of leukemias (such as specific chronic leukemias defined by specific translocations or point mutations) but are much more difficult to define for normal karyotype AML. For example, expression of the AML1-ETO fusion transcript, generated by the common t(8;21) translocation in AML, can be detected not only in leukemic cells but also in normal HSCs from patients in clinical remission from AML. However, these AML1 ETO-expressing HSCs are not leukemic and can differentiate into myeloid and erythroid cells in vitro in a manner similar to HSCs without the AML1-ETO fusion transcripts (see Fig. 1). Similarly, analysis of mice expressing the AML1-ETO fusion from the endogenous Aml1 locus in vivo has revealed that AML1-ETO-expressing HSCs have aberrant self-renewal capacity but do not develop overt leukemia unless additional genetic abnormalities are present. These data strongly suggest that the acquisition of additional genetic abnormalities in a subset of HSCs or their progeny is required to give rise to overt leukemia. In these studies, the HSCs bearing the AML1 ETO fusion reside within the Lin−CD34+CD38− subpopulation that is also the immunophenotype of normal human HSCs, suggesting that the initiating lesion must occur in a cell with an immunophenotype of normal HSCs. However, leukemic cells from 30% to 40% of patients with AML do not express CD34, and LICs from some patients with AML can actually be CD34−. Interestingly, prior work evaluating the location of the PML-RARA transcript present in acute promyelocytic leukemia (APL) revealed that the PML-RARA trans location is actually present in CD34−CD38+ populations and not in CD34+CD38− HSC-enriched populations (see Fig. 1). These data clearly reveal that there is enormous heterogeneity in the cell-of origin of AML.
Advancement in techniques to map genetic alterations in cancer has allowed for much finer tracking of somatic mutations in AML and other hematopoietic malignancies with a normal karyotype. It is now believed that an average of five coding mutations is present in adults with de novo AML. Several groups have now studied the occurrence of somatic mutations in bulk AML cells and the remaining seemingly nonaffected HSCs. This work has clearly shown that the HSC compartment in patients with AML contains HSCs with none of the mutations found in the AML as well as HSCs with various combinations of genetic alterations similar to that present in the bulk malignant cells (see Fig. 1). These latter HSCs are now understood to be “preleukemic stem cells” that initiate AML and can also be identified in remission samples, indicating that they are able to survive induction chemotherapy (see box on Preleukemic Stem Cells). Many of the mutations that occur in preleukemic HSCs confer growth properties that allow them to outcompete nor mal HSCs and presumably lead to relapse. Interestingly, mutations occurring in preleukemic HSCs are enriched in genes regulating DNA methylation, chromatin modifications, and the cohesin complex, while genetic alterations activating signaling are often present in more downstream overt malignant cells and absent from preleukemic HSCs. A series of recent studies performing single-cell mutational analysis of AML have further solidified these findings and identified that mutations in signaling genes (such as FLT3, NRAS, and KRAS) are often acquired in subclones of AML and can be acquired in multiple distinct subclones.
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