Showing papers by "Xiaoyan Jiang published in 2007"

Chronic myeloid leukemia stem cells possess multiple unique features of resistance to BCR-ABL targeted therapies.

Abstract: The leukemic stem cells in patients with chronic myeloid leukemia (CML) are well known to be clinically resistant to conventional chemotherapy and may also be relatively resistant to BCR-ABL-targeted drugs. Here we show that the lesser effect of imatinib mesylate (IM) on the 3-week output of cells produced in vitro from lin(-)CD34(+)CD38(-) CML (stem) cells compared with cultures initiated with the CD38(+) subset of lin(-)CD34(+) cells is markedly enhanced (>10-fold) when conditions of reduced growth factor stimulation are used. Quantitative analysis of genes expressed in these different CML subsets revealed a differentiation-associated decrease in IL-3 and G-CSF transcripts, a much more profound decrease in expression of BCR-ABL than predicted by changes in BCR expression, decreasing expression of ABCB1/MDR and ABCG2 and increasing expression of OCT1. p210(BCR-ABL) and kinase activity were also higher in the lin(-)CD34(+)CD38(-) cells and formal evidence that increasing BCR-ABL expression decreases IM sensitivity was obtained from experiments with a cell line model. Nevertheless, within the entire CD34(+) subset of CML cells, BCR-ABL expression was not strongly affected by changes in cell cycle status. Taken together, these results provide the first evidence of multiple mechanisms of innate IM resistance in primitive and quiescent CML cells.

Instability of BCR–ABL Gene in Primary and Cultured Chronic Myeloid Leukemia Stem Cells

Abstract: Background Imatinib mesylate treatment causes remissions in a majority of patients with chronic myeloid leukemia (CML), but relapses are an increasing problem. We hypothesized that imatinib-resistant leukemic cells emerge from CML stem cells that acquire BCR-ABL gene mutations even before exposure to BCR-ABL-targeted agents such as imatinib. Methods Lineage-negative (i.e., immature) CD34+ CD38- CML stem cell-enriched populations were isolated from five patients with chronic phase CML samples by fluorescence-activated cell sorting. To identify BCR-ABL gene mutations, complementary DNAs (cDNAs) prepared from purified CML stem cells were subjected to allele-specific amplification using primers corresponding to 16 kinase domain mutations, with normal bone marrow cells serving as negative controls. We also cloned and directly sequenced BCR-ABL cDNAs prepared from freshly isolated CML stem cells and from their progeny generated after 3-5 weeks of culture. Results In 20%-33% of cDNA preparations from freshly isolated CML stem cell-enriched populations, both allele-specific amplification and direct sequencing methods revealed mutations in sequences corresponding to the BCR-ABL kinase domain. Mutations were not observed in cDNA sequences encoding the c-ABL kinase domain that were obtained from similar types of primitive normal cells. More than 70 different BCR-ABL mutations (including frameshift mutations and premature stop codons) were identified in the progeny of cultured CML stem cells. Analysis of individual clones derived from the cultured cells demonstrated that new BCR-ABL mutations were produced. Conclusions Primary CML stem cells display instability of the BCR-ABL fusion gene both in vivo and in vitro. Thus, patients may possess leukemic stem cells with BCR-ABL kinase mutations before initiation of BCR-ABL-targeted therapies and would likely be predisposed to develop resistance to these agents.

The Challenges of Targeting Chronic Myeloid Leukemia Stem Cells

Abstract: Chronic myeloid leukemia (CML) is sustained by a clonally amplified population of Bcr Abl-positive pluripotent stem cells. Persistence of a large, functionally intact yet suppressed residual normal hematopoietic stem cell population in most patients with CML has made it possible to aim at the development of curative therapies. However, achieving this goal requires the identification of agents that will eradicate the leukemic stem cell population. Several potent Bcr-Abl-targeted drugs have now been introduced into clinical practice with remarkable effects. Nevertheless, accumulating data indicate that the leukemic CML stem cells in patients with chronic phase CML are less responsive to these agents than the bulk of the neoplastic cells. In this article, we review emerging evidence that CML stem cells have a number of unusual properties that underlie their relative insensitivity to treatment, including those that specifically target the Bcr-Abl oncoprotein. The biology of the neoplastic stem cells in patients with CML is clearly important to the future attainment of cures and might also prove a paradigm relevant to other types of malignancies that are sustained by transformed stem cell populations.