Acute Lymphoblastic 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 , P152-153
2025-10-27
44
Unlike the myeloid malignancies, it has been less clear whether lymphoid malignancies also arise from an HSC or have a different cell of-origin. In B-cell acute lymphoblastic leukemia (B-ALL), considerable effort has gone into answering this question (Fig. 1). Early studies in specific subtypes of B-ALL supported a preleukemic stem cell such as identified in AML. TEL/AML-1 rear ranged ALL has been particularly well studied and is associated with a good prognosis. These studies showed that TEL/AML-1 alone is insufficient for leukemogenesis. In fact, the frequency of TEL/AML-1 in healthy infants far exceeds the incidence of ALL, suggesting that the development of leukemia requires a second hit. This is evident from studies of pairs of twins, both with evidence of a preleukemic TEL/ AML-1 CD34+CD38−CD19+ population of cells, where one twin developed ALL and the other did not. The healthy twin retained the preleukemic population, which showed evidence of self-renewal and hierarchical differentiation. Later studies of high-risk ALL showed that leukemogenic potential may also be present in more differentiated cell populations, such as CD34−CD19+ cells (see Fig. 1). Recent extension of this work to B-ALL cases with a variety of chromosomal abnormalities has found that even mature blasts expressing CD20 were able to establish leukemia upon transplantation into immunodeficient mice. Also, as many as 1 in 40 B-ALL blasts retained leukemogenic potential. Overall, B-ALL blasts do not seem to be hierarchically arranged in a similar fashion as AML, and engraftment of further differentiated CD34− blasts can give rise to both CD34− and CD34+ populations in vivo.30 Together, these data suggest that B-ALL arises in a committed lymphoid progenitor rather than only a small population of cells accumulating mutations and retaining stem cell properties and that most or even all of the leukemic blasts retain the ability to propagate the malignancy.
Fig1. 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 immune-deficient mice, it appears that multiple blast populations in B-ALL are able to establish the disease in immune-deficient mice. For example, CD34+CD19+ blasts as well as CD34−CD19+ blasts from individual patients have been shown to be able to 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.
In contrast to TEL/AML-1, those patients with ALL carrying the BCR-ABL fusion protein have much worse clinical outcomes. However, like TEL/AML-1, BCR-ABL is also thought to be a primary mutation that is necessary but not sufficient for ALL transformation. Interestingly, the two BCR-ABL transcripts, P190 and P210, caused by different break points in the t(9;22) translocation, show distinct patterns of HSC and committed B-cell pro genitor involvement. In most cases, the P190 BCR-ABL originates in a CD34+CD38−CD19+ progenitor cell while P210 BCR-ABL originates in a multipotent HSC. When purified P210 BCR-ABL HSCs were transplanted into NOD/SCID mice, they exclusively reconstituted normal, BCR-ABL–negative multilineage hematopoiesis. These data suggest that the purified HSC also contain normal HSCs that outcompete the P210 BCR-ABL HSCs, which are not the leukemia stem cells. In contrast, more committed CD19+ P210 BCR-ABL–positive cells resulted in leukemic reconstitution upon transplantation into NOD/SCID mice that was enhanced following secondary transplant. These data complement recent findings suggesting that the primary BCR-ABL translocation in CML originates in HSCs, yet the leukemic transformation in blast crisis results in an LSC with a committed progenitor cell phenotype. This begs the question of whether P210 BCR-ABL–positive ALL represents de novo ALL or CML in lymphoid blast crisis.
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