Leukemia stem cells in a genetically defined murine model of blast-crisis CML.

Myeloid leukemia arises from leukemia stem cells (LSCs), which are resistant to standard chemotherapy agents and likely to be a major cause of drug-resistant disease and relapse. To investigate the in vivo properties of LSCs, we developed a mouse model in which the biologic features of human LSCs are closely mimicked. Primitive normal hematopoietic cells were modified to express the BCR/ABL and Nup98/HoxA9 translocation products, and a distinct LSC population, with the aberrant immunophenotype of lineage(-), Kit(+/-), Flt3(+), Sca(+), CD34(+), and CD150(-), was identified. In vivo studies were then performed to assess the response of LSCs to therapeutic insult. Treatment of animals with the ABL kinase inhibitor imatinib mesylate induced specific modulation of blasts and progenitor cells but not stem- cell populations, thereby recapitulating events inferred to occur in human chronic myelogenous leukemia (CML) patients. In addition, challenge of leukemic mice with total body irradiation was selectively toxic to normal hematopoietic stem cells (HSCs), suggesting that LSCs are resistant to apoptosis and/or senescence in vivo. Taken together, the system provides a powerful means by which the in vivo behavior of LSCs versus HSCs can be characterized and candidate treatment regimens can be optimized for maximal specificity toward primitive leukemia cells.

Stem cells, aging, and cancer: inevitabilities and outcomes.

Given the unique abilities of a stem cell to self-renew, differentiate, and proliferate, it is no wonder that they are critically important to an organism during development and to maintain homeostasis. Likewise, when something goes awry within a stem cell, it is likely to have far-reaching effects, since stem cells persist throughout the lifetime of the individual. Two significant biological phenomena that involve stem cells are the inevitable process of aging and a major health issue whose incidence increases with aging: cancer. In this review, we summarize evidence and theories concerning these two stem cell processes. The inability of stem cells to be passaged indefinitely in mice and the data supporting regular replication of the quiescent stem cell pool are discussed. Further, the current evidence indicating a stem cell origin of acute myeloid leukemia, including examples from both experimental mouse models and human clinical samples, is evaluated. Finally, we propose a model in which aging of the stem cell population of the hematopoietic system in particular can create conditions that are permissive to leukemia development; in fact, we suggest that aging is a secondary event in leukemogenesis.

Polymorphisms in the MLL breakpoint cluster region (BCR).

The MLL gene is involved in many chromosomal translocations leading to both acute myeloid and lymphoid leukemia. Some patients treated for primary malignancies with chemotherapeutic agents that inhibit DNA topoisomerase II (topo II) develop treatment-related leukemia (t-AML) caused by MLL gene rearrangement. Whether these patients are unusually susceptible to anti-topo II drugs, or whether this is a random adverse event is unknown. To discover genetic polymorphisms that may predispose patients to t-AML development, we sequenced the 8.3-kb MLL breakpoint cluster region (BCR) from 22 patients who had been treated with topo II inhibitors and who developed t-AML and from 37 patients who did not, and from eight infants and 20 normal individuals. Four polymorphic sites within Alu repetitive elements were identified; three affected the length of poly-A tracts and one altered the size of a trinucleotide repeat. The three poly-A tract polymorphisms occurred with equal frequency in leukemic patients and controls and hence are not predictors of risk. The trinucleotide GAA repeat has three alleles: (GAA)4, (GAA)5, and (GAA)6. The (GAA)6 allele is very rare. The adult t-AML patients are almost exclusively (GAA)4/5 heterozygotes (83%), whereas the normal population is only 55% (GAA)4/5 heterozygotic and is represented equally by (GAA)4 and (GAA)5 homozygotes (20% each). Only certain trends could be established because of the small sample size of these leukemic groups. Whereas adult t-AML patients are more likely to be (GAA)4/5 heterozygotes, this is not statistically significant, and this polymorphism within the MLL BCR has only a suggestive association with t-AML development.