Chronic myelocytic leukemia: Clonal origin in a stem cell common to the granulocyte, erythrocyte, platelet and monocyte/macrophage

Fialkow, Philip J.; Jacobson, Robert J.; Papayannopoulou, Thalia

doi:10.1016/0002-9343(77)90124-3

Cited by 819 publications

(275 citation statements)

References 26 publications

Supporting

Mentioning

261

Contrasting

Unclassified

Order By: Relevance

“…A hallmark of CML is the expansion of immature progenitor cells of the myeloid lineage in the bone marrow compartment, so that the majority of peripheral circulating CD34 + cells from CML patients are myeloid (Fialkow et al, 1977). PSCs were harvested from suspension cultures, washed and plated on semi-solid methylcellulose plates supplemented with a cocktail of GFs conducive to erythroid colony formation (McGuckin et al, 1996).…”

Section: Molecular and Cellular Pathologymentioning

confidence: 99%

The in vitro activity of the tyrosine kinase inhibitor STI571 in BCR–ABL positive chronic myeloid leukaemia cells: synergistic interactions with anti-leukaemic agents

2002

View full text Add to dashboard Cite

Chronic myeloid leukaemia is typically characterised by the presence of dysregulated BCR -ABL tyrosine kinase activity, which is central to the oncogenic feature of being resistant to a wide range of cytotoxic agents. We have investigated whether the inhibition of this tyrosine kinase by the novel compound STI571 (formerly CGP57148B) would render K562, KU812 cell lines and chronic myeloid leukaemia-progenitor cells sensitive to induction of cell kill. Proliferation assays showed STI571 to be an effective cytotoxic agent in chronic myeloid leukaemia-derived cell lines (IC 50 on day 5 of 4.6 mg ml 71 and 3.4 mg ml 71 for K562 and KU812 respectively) and in leukaemic blast cells (per cent viability on day 3 at 4 mg ml 71 : 55.5+8.7 vs 96.4+3.7%). STI571 also appeared to specifically target bcr -abl expressing cells, as results from colony forming assays using the surviving cell fraction from STI571-treated peripheral CD34 + chronic myeloid leukaemia blast cells, indicated a reduction in the expansion of colonies of myeloid lineage, but no effect on normal colony formation. Our data also showed synergy between STI571 and other anti-leukaemic agents; as an example, there were significant increases in per cent cell kill in cell lines cultured with both STI571 and etoposide compared to the two alone (per cent cell kill on day 3: 73.7+11.3 vs 44.5+8.7 and 17.8+7.0% in cultures with STI571 and etoposide alone respectively; P50.001). This study confirms the central oncogenic role of BCR -ABL in the pathogenesis of chronic myeloid leukaemia, and highlights the role of targeting this tyrosine kinase as a useful tool in the clinical management of the disease.

show abstract

Section: Molecular and Cellular Pathologymentioning

confidence: 99%

The in vitro activity of the tyrosine kinase inhibitor STI571 in BCR–ABL positive chronic myeloid leukaemia cells: synergistic interactions with anti-leukaemic agents

2002

View full text Add to dashboard Cite

show abstract

“…Standard LTBMC were established in 25 cm 2 tissue flasks Eligibility with a preliminary sample of marrow from each patient to The following criteria were applied: (1) Ph+ CML in evaluate the genotype of clonogenic cells and mature end chronic phase; (2) Ͻ50 years old; (3) lack of an HLAcells. Cells were inoculated in a 10 ml volume of culture matched sibling donor; and (4) previous evidence in longmedium at a concentration of 2 × 10 6 nucleated cells/ml and term bone marrow cultures (LTBMC) of the presence of the cultures were maintained for 4-5 weeks.…”

Section: Culture Assaysmentioning

confidence: 99%

Autografting in Philadelphia (Ph)+ chronic myeloid leukaemia using cultured marrow: an update of a pilot study

Coutinho

Chang

Brereton

et al. 1997

Bone Marrow Transplant

View full text Add to dashboard Cite

Summary:dividing haemopoietic cells of non-lymphoid lineages and, in some patients, also in B lymphocytes. 2,3 Incubation of CML marrow in long-term culture (LTC)The haematological manifestation of the disease can be conditions may result in selection of normal (Ph−) LTCeasily controlled with cytotoxic drugs, such as busulphan initiating cells (LTC-IC) as early as 10 days, and in proand hydroxyurea, but there is little evidence that they delay duction of Ph− clonogenic cells and mature end cells further progression to accelerated or blastic phase. 4 Howwithin 5 weeks. This was the rationale for using marrow ever, interferon-␣ has been reported to delay disease procells from 10-day-old LTC to autograft nine chronic gression and improve survival in CML, 5,6 and in a small phase CML patients, ineligible for HLA-matched sibproportion of patients to induce partial or complete cytoling donor transplant, and who were selected on the genetic remission. 7 basis of a pre-transplant screening LTC test. Of the Allogeneic bone marrow transplantation, by inducing transplanted patients three died; two of graft failure complete eradication or at least long-term suppression of and one of therapy-related toxicity with 97% Ph− cells the Ph+ clone, constitutes the most effective option and the 16 months following the autograft. The reconstituting only known curative treatment in CML. 8,9 However, it can haemopoietic cells in the seven engrafted patients were only be offered to a small proportion of patients because 100% Ph− in four, у 90% Ph− in two and 71% Ph− of lack of a suitable donor or advanced age. For patients in the seventh, with a duration of complete cytogenetic aged less than 50 years, only 15% have HLA-matched sibresponse of 6-12 months. Three patients reverted to ling donors. 4 The role of matched unrelated donor transchronic phase and 100% Ph+ haemopoiesis 27-36 plants remains uncertain, but the procedure may be useful months post-autograft. The other three patients remain for young patients. 10 in continuous haematological remission with 22% Ph− A recent multicentre analysis of autologous transplants cells in one and complete cytogenetic remission in the in CML suggested that autografting might be a possible other two 3-4 years post-autograft. IFN therapy was alternative for many of these patients. 11 The preliminary generally introduced on the first evidence of recurrence results for patients autografted in first chronic phase indiof Ph+ cells or of cytogenetic deterioration. Further cate a survival plateau of 58% up to 7 years. Although not strategies to modulate immune surveillance in vivo may curative, the survival may be better than that achieved by improve the outcome of cultured marrow autografts treatment with conventional drugs or IFN-␣. which give an initial and rather prolonged bias towards Long-lasting molecular remissions have been docuPh− haemopoiesis.mented in syngeneic transplants despite the lack of graft-

show abstract

“…Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder of primitive pluripotent stem cells involving all hematopoietic lineages (Fialkow et al, 1977). The Philadelphia chromosome (Ph) is the cytogenetic hallmark of CML (Rowley, 1973).…”

Section: Introductionmentioning

confidence: 99%

Mutator phenotype of BCR – ABL transfected Ba/F3 cell lines and its association with enhanced expression of DNA polymerase β

et al. 1999

View full text Add to dashboard Cite

Chronic myelogenous leukemia (CML) is characterized by the Philadelphia chromosome resulting from the translocation t(9-22) producing the chimeric 190 and 210 kDa BCR ± ABL fusion proteins. Evolution of the CML to the more agressive acute myelogenous leukemia (AML) is accompanied by increased cellular proliferation and genomic instability at the cytogenetic level. We hypothezised that genomic instability at the nucleotide level and spontaneous error in DNA replication may also contribute to the evolution of CML to AML. Murine Ba/F3 cell line was transfected with the p190 and p210-encoding BCR ± ABL oncogenes, and spontaneous mutation frequency at the Na-K-ATPase and the hypoxanthine guanine phosphoribosyl transferase (HPRT) loci were measured. A signi®cant 3 ± 5-fold increase in mutation frequency for the transfected cells relative to the untransfected control cells was found. Furthermore, we observed that BCR ± ABL transfection induced an overexpression of DNA polymerase b, the most inaccurate of the mammalian DNA polymerases, as well as an increase in its activity, suggesting that inaccuracy of DNA replication may account for the observed mutator phenotype. These data suggest that the Philadelphia abnormality confers a mutator phenotype and may have implications for the potential role of DNA polymerase b in this process.

show abstract

Chronic myelocytic leukemia: Clonal origin in a stem cell common to the granulocyte, erythrocyte, platelet and monocyte/macrophage

Cited by 819 publications

References 26 publications

The in vitro activity of the tyrosine kinase inhibitor STI571 in BCR–ABL positive chronic myeloid leukaemia cells: synergistic interactions with anti-leukaemic agents

The in vitro activity of the tyrosine kinase inhibitor STI571 in BCR–ABL positive chronic myeloid leukaemia cells: synergistic interactions with anti-leukaemic agents

Autografting in Philadelphia (Ph)+ chronic myeloid leukaemia using cultured marrow: an update of a pilot study

Mutator phenotype of BCR – ABL transfected Ba/F3 cell lines and its association with enhanced expression of DNA polymerase β

Contact Info

Product

Resources

About