Clonal chromosomal abnormalities in the stem cell compartment of patients with acute myeloid leukemia in morphological complete remission

Feuring‐Buske, Michaela; Haase, Detlef; Buske, Christian; Hiddemann, Wolfgang; Wörmann, Bernhard

doi:10.1038/sj.leu.2401300

Cited by 20 publications

(9 citation statements)

References 21 publications

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“…BCRP expression in CD34+38À cells in AML was not significantly different from the expression in these cells in normal bone marrow (P = 0.30). These results indicate that BCRP is preferentially expressed in primitive CD34+38À cells in the majority of AML samples, similar to the expression profile in The CD34+38À cell population in AML harbors residual normal CD34+38À cells (27). To exclude the possibility that the expression and function of ABCG2 is present in residual normal cells, rather than leukemic cells, within the CD34+38À cell compartment in AML, we did fluorescence in situ hybridization analysis on leukemia-associated cytogenetic aberrations in these cells (n = 5).…”

Section: Breast Cancer Resistance Protein Expression and Functionsupporting

confidence: 70%

Breast Cancer Resistance Protein in Drug Resistance of Primitive CD34+38− Cells in Acute Myeloid Leukemia

Raaijmakers¹,

Grouw²,

Heuver³

et al. 2005

Clinical Cancer Research

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Purpose: Acute myeloid leukemia (AML) is considered a stem cell disease. Incomplete chemotherapeutic eradication of leukemic CD34+38À À stem cells is likely to result in disease relapse. The purpose of this study was to investigate the role of the breast cancer resistance protein (BCRP/ATP-binding cassette, subfamily G, member 2) in drug resistance of leukemic stem cells and the effect of its modulation on stem cell eradication in AML.Experimental Design: BCRP expression (measured flowcytometrically using the BXP21 monoclonal antibody) and the effect of its modulation (using the novel fumitremorgin C analogue KO143) on intracellular mitoxantrone accumulation and in vitro chemosensitivity were assessed in leukemic CD34+38À À cells.Results: BCRP was preferentially expressed in leukemic CD34+38À À cells and blockage of BCRP-mediated drug extrusion by the novel fumitremorgin C analogue KO143 resulted in increased intracellular mitoxantrone accumulation in these cells in the majority of patients. This increase, however, was much lower than in the mitoxantrone-resistant breast cancer cell line MCF7-MR and significant drug extrusion occurred in the presence of BCRP blockage due to the presence of additional drug transport mechanisms, among which ABCB1 and multiple drug resistance protein. In line with these findings, selective blockage of BCRP by KO143 did not enhance in vitro chemosensitivity of leukemic CD34+38À À cells.Conclusions: These results show that drug extrusion from leukemic stem cells is mediated by the promiscuous action of BCRP and additional transporters. Broadspectrum inhibition, rather than modulation of single mechanisms, is therefore likely to be required to circumvent drug resistance and eradicate leukemic stem cells in AML.

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Section: Breast Cancer Resistance Protein Expression and Functionsupporting

confidence: 70%

Breast Cancer Resistance Protein in Drug Resistance of Primitive CD34+38− Cells in Acute Myeloid Leukemia

Raaijmakers¹,

Grouw²,

Heuver³

et al. 2005

Clinical Cancer Research

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“…With this procedure, we and others were able to show by FISH that primary tumours and synchronous or metachronous locoregional or distant metastases exhibit nearly identical patterns of numeric chromosomal aberrations (Simpson et al, 1996;Fiegl et al, 2000;Fehm et al, 2002). Second, enrichment steps like flow cytometry or immunobead selection can be applied prior to FISH analysis in order to deplete the reactive cellular background (Feuring-Buske et al, 1999;Sakaguchi et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Sensitive detection of tumour cells in effusions by combining cytology and fluorescence in situ hybridisation (FISH)

et al. 2004

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Diagnosis of malignant cells in effusions is important for staging procedures and resulting therapeutic decisions. Cytodiagnostics in effusions is sometimes difficult since reactive mesothelial cells can mimic malignant cells. We used fluorescence in situ hybridisation (FISH) in single-colour or if appropriate in dual-colour evaluation to detect chromosomal aberrations in effusion cells as markers of malignancy, to raise the diagnostic yield. Cytologic and FISH evaluations -by using probes representing several chromosomes always including chromosomes 11 and 17 -were performed in 358 effusion fluids. Cytology was positive for malignancy in 44.4% of all effusions, whereas FISH was positive in 53.9% (P ¼ 0.0001). The combination of cytology and FISH was diagnostic for malignancy in 60.9% of effusions. Diagnostic superiority of FISH was demonstrated in effusions from breast cancer, lung cancer, pancreatic cancer, and in effusions from the entire group of gynaecological and gastrointestinal carcinomas. In transudates (effusion protein o2.5 g dl À1 ), malignant cells were detectable by cytology, FISH, and combined use of both methods in 18.6, 30, and 37.1% of effusions, respectively, suggesting that cytologic and molecular analysis should be performed also with transudates. In conclusion, FISH in combination with conventional cytology is a highly sensitive and specific diagnostic tool for detecting malignant cells in effusions.

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“…Für die Praxis gilt, dass bei der Mehrzahl der Patienten mit AML sowohl leukämische als auch normale Stammzellen vorhanden sind und dass der leukämische Klon auch in morphologisch kompletter Remission nach Polychemotherapie persistieren kann [20]. Die Entwicklung innovativer therapeutischer Konzepte muss daher darauf ausgerichtet sein, möglichst effektiv und selektiv LSCs zu eliminieren.…”

Section: Die Ursprungszelle Der Amlunclassified

Pathogenese und Biologie der akuten myeloischen Leukämie

Christ¹,

Feuring‐Buske²,

Hiddemann³

et al. 2007

Med Klin

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Acute myeloid leukemia (AML) arises from the clonal expansion of primitive myeloid precursor cells. A series of genetic alterations leads to a perturbation of normal developmental programs affecting growth, maturation and differentiation of hematopoietic cells. As a consequence, immature leukemic cells that have the ability to divide and proliferate, but lack normal differentiation mechanisms, accumulate in the bone marrow. This, in turn, leads to a severe impairment of normal hematopoiesis. Over the last several years, a number of clinical and basic research studies have elucidated important pathogenetic mechanisms leading to the initiation of AML. The identification of numerous chromosomal aberrations and mutations specific for AML has deepened our insights into the biology of AML and has allowed to improve our diagnostic tools, the definition of prognostic subgroups and therapeutic concepts.

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Clonal chromosomal abnormalities in the stem cell compartment of patients with acute myeloid leukemia in morphological complete remission

Cited by 20 publications

References 21 publications

Breast Cancer Resistance Protein in Drug Resistance of Primitive CD34+38− Cells in Acute Myeloid Leukemia

Breast Cancer Resistance Protein in Drug Resistance of Primitive CD34+38− Cells in Acute Myeloid Leukemia

Sensitive detection of tumour cells in effusions by combining cytology and fluorescence in situ hybridisation (FISH)

Pathogenese und Biologie der akuten myeloischen Leukämie

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