Investigating human leukemogenesis: from cell lines to in vivo models of human leukemia

Abstract

The hematopoietic system produces appropriate levels of blood cells over an individual's lifetime through a careful balance of differentiation, proliferation and self-renewal. The acquisition of genetic and epigenetic alterations leads to deregulation of these processes and the development of acute leukemias. A prerequisite to targeted therapies directed against these malignancies is a thorough understanding of the processes that subvert the normal developmental program of the hematopoietic system. This involves identifying the molecular lesions responsible for malignant transformation, their mechanisms of action and the cell type(s) in which they occur. Over the last 3 decades, significant progress has been made through the identification of recurrent genetic alterations and translocations in leukemic blast populations, and their subsequent functional characterization in cell lines and/or mouse models. Recently, primary human hematopoietic cells have emerged as a complementary means to characterize leukemic oncogenes. This approach enables the process of leukemogenesis to be precisely modeled in the appropriate cellular context: from primary human hematopoietic cells to leukemic stem cells capable of initiating disease in vivo.Here we review the model systems used to study leukemogenesis, and focus particularly on recent advances provided by in vitro and in vivo studies with primary human hematopoietic cells.

Identification of T-lymphocytic leukemia–initiating stem cells residing in a small subset of patients with acute myeloid leukemic disease

“…Lineage plasticity in xenotransplantation mouse models has also been described in other MLL-fusion protein-transduced human primitive hematopoietic cell fraction. 36,43 Nonetheless, the mechanism underlying this lineage plasticity remains unclear, as do the targets of MLL fusion products. 44 Regardless of the mouse strain used, the ability to engraft immunodeficient mice seems to be inherent to transplanted cells or to some other unknown microenvironmental parameters.…”

In vivo efficacy of the recombinant anti‐CD64 immunotoxin H22(scFv)‐ETA′ in a human acute myeloid leukemia xenograft tumor model

“…1 In younger patients, AML chemotherapy using anthracyclines and cytarabin results in 60-70% complete remission, but the median age for primary AML is >70 years and intensive chemotherapy is not recommended in older patients. 2 Furthermore, the drugs discriminate poorly between malignant and normal cells resulting in severe off-target effects.…”

Identification of AKN-032, a novel 2-aminopyrazine tyrosine kinase inhibitor, with significant preclinical activity in acute myeloid leukemia

“…MV4-11 is an excellent model system for FLT3 mutated AML [40], but as a cell line, it is likely to have acquired additional genetic changes in becoming immortalized and adapted for continual growth [41]. Although being essential for investigation on mechanism of action of cytotoxic drugs and valuable tools in drug discovery, cell lines may have limitations when it comes to predicting clinical outcome [42,43].…”