Treatment with interferon-alpha preferentially reduces the capacity for amplification of granulocyte-macrophage progenitors (CFU-GM) from patients with chronic myeloid leukemia but spares normal CFU-GM.

Gordon, Myrtle Y.; Marley, Stephen B.; Lewis, John L.; Davidson, RJ; Nguyen, D.; Grand, F. H.; Amos, Tim; Goldman, John M.

doi:10.1172/jci3094

Cited by 67 publications

(74 citation statements)

References 27 publications

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“…At this concentration, neither the AUC of NBM nor that of CML CFU-GM was significantly reduced (Figure 2). In confirmation of previously reported results, 11 the AUC of NBM CFU-GM was not altered by growing the colonies in the presence of 100 U/ml IFN-␣ (100 ± 8.2% of controls; P = 0.9) whilst the AUC of CML CFU-GM was significantly reduced (60 ± 7% of controls; P = 0.03). When CFU-GM were grown in the presence of 0.5 ng/ml Ara-C + 100 U/ml IFN-␣, there was a significant reduction in the NBM AUC to 50 ± 10% of control values (P = 0.03) whereas for CML CFU-GM the addition of Ara-C to IFN-␣ did not further reduce the AUC.…”

Section: Cfu-gm Self-replicationsupporting

confidence: 91%

“…11 This finding provided the first evidence for a selective inhibitory effect of IFN-␣ on CML progenitor cell kinetics. More recently, we have found that the tyrosine kinase inhibitor, STI571, also preferentially suppresses the replating ability of CML CFU-GM.…”

Section: Introductionmentioning

confidence: 68%

“…Each colony was vigorously dispersed in a separate well of a 96-well microtitre plate containing 100 l of methylcellulose plus serum and cytokines as previously detailed. 11 The plates were incubated for a further 7 days at 37°C in humidified 5% CO 2…”

Section: Cfu-gm Replating Assay Secondary Colony Formationmentioning

confidence: 99%

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Combination of interferon alpha with either Ara-C or ATRA in vitro reduces the selective action of interferon against CML CFU-GM

et al. 2000

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Section: Cfu-gm Self-replicationsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 68%

See 1 more Smart Citation

Combination of interferon alpha with either Ara-C or ATRA in vitro reduces the selective action of interferon against CML CFU-GM

et al. 2000

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“…31 This idea led us to establish the CFU-GM replating assay in order to measure the self-renewal of CFU-GM in various circumstances. 33 The increased replating ability of CFU-GM in PBPC harvests, compared with bone marrow CFU-GM, is therefore consistent with the more rapid rate of neutrophil recovery in recipients of PBPC since whilst a shift in emphasis to self-renewal at progenitor level would briefly reduce the emergence of neutrophils, the amplification potential between CFU-GM and neutrophil is such that even small numerical changes in the progenitor population can have a very large effect on neutrophil output.…”

Section: Discussionmentioning

confidence: 69%

“…[30][31][32] We have developed in vitro assays to measure the balance between self-renewal and differentiation of haemopoietic progenitor cells. These are based on secondary colony formation by replated CFU-GM colonies for the myeloid lineage; 33 for the erythroid lineage, the assay is based on subcolony formation during erythroid burst formation. 34 Using these assays, we have demonstrated that selfrenewal in both the erythroid and myeloid progenitor populations varies according to tissue source and is modulated by external factors such as cytokines.…”

mentioning

confidence: 99%

Peripheral blood progenitor cell mobilisation alters myeloid, but not erythroid, progenitor cell self-renewal kinetics

Marley

Lewis

Zheng

et al. 2001

Bone Marrow Transplant

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Summary:Transplantation of progenitor cells which have been mobilised into the bloodstream (PBPC) following the administration of G-CSF results in more rapid neutrophil recovery than transplantation of bone marrow (BM). The reasons for the accelerated neutrophil engraftment are not clear, but would be explained by increased self-replication of myeloid progenitor cells (CFU-GM). We have used a CFU-GM replating assay to investigate myeloid progenitor self-replication, and quantification of subcolony formation during erythroid burst formation to quantify erythroid progenitor selfrenewal. Secondary colony formation by CFU-GM, grown from PBPC and then replated was increased compared with secondary colony formation by BM CFU-GM (P = 0.0001); erythroid subcolony formation was not altered. There was no difference between the replating abilities of PBPC CFU-GM derived from allogeneic donors (normal individuals) and autologous donors (patients with malignant disease) although differences were found between subgroups of autologous donors. The increased replication of PBPC could not be accounted for by a reduction in progenitor cell apoptosis; PBPC CFU-GM contained slightly fewer apoptotic CD34 ؉ cells than BM CFU-GM. The increased replication by PBPC CFU-GM was reversible because it declined when CFU-GM colonies were passaged through three sequential CFU-GM replating cycles. This decline in self-replication was more rapid than the decline seen in replated BM CFU-GM. The self-replication of PBPC CFU-GM, and subcolony formation by BFU-E could be further enhanced by exposure to cytokines in vitro. We conclude that mobilisation alters the replication kinetics of myeloid, but not of erythroid, progenitor cells, that mobilisation-induced events are of limited duration and that in vitro exposure

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Effective targeting of chronic myeloid leukemia initiating activity with the combination of arsenic trioxide and interferon alpha

Iskandarani

Saliba

et al. 2013

Intl Journal of Cancer

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Imatinib is the standard of care in chronic meloid leukemia (CML) therapy. However, imatinib is not curative since most patients who discontinue therapy relapse indicating that leukemia initiating cells (LIC) are resistant. Interferon alpha (IFN) induces hematologic and cytogenetic remissions and interestingly, improved outcome was reported with the combination of interferon and imatinib. Arsenic trioxide was suggested to decrease CML LIC. We investigated the effects of arsenic and IFN on human CML cell lines or primary cells and the bone marrow retroviral transduction=transplantation murine CML model. In vitro, the combination of arsenic and IFN inhibited proliferation and activated apoptosis. Importantly, arsenic and IFN synergistically reduced the clonogenic activity of primary bone marrow cells derived from CML patients. Finally, in vivo, combined interferon and arsenic treatment, but not single agents, prolonged the survival of primary CML mice. Importantly, the combination severely impaired engraftment into untreated secondary recipients, with some recipients never developing the disease, demonstrating a dramatic decrease in CML LIC activity. Arsenic=IFN effect on CML LIC activity was significantly superior to that of imatinib. These results support further exploration of this combination, alone or with imatinib aiming at achieving CML eradication rather than long-term disease control.

show abstract

Treatment with interferon-alpha preferentially reduces the capacity for amplification of granulocyte-macrophage progenitors (CFU-GM) from patients with chronic myeloid leukemia but spares normal CFU-GM.

Cited by 67 publications

References 27 publications

Combination of interferon alpha with either Ara-C or ATRA in vitro reduces the selective action of interferon against CML CFU-GM

Combination of interferon alpha with either Ara-C or ATRA in vitro reduces the selective action of interferon against CML CFU-GM

Peripheral blood progenitor cell mobilisation alters myeloid, but not erythroid, progenitor cell self-renewal kinetics

Effective targeting of chronic myeloid leukemia initiating activity with the combination of arsenic trioxide and interferon alpha

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