Analysis of interferon-inducible genes in cells of chronic myeloid leukemia patients responsive or resistant to an interferon-alpha treatment

Clauss, Isabelle M.; Vandenplas, B; Wathelet, Marc; Dorval, C; Delforge, Alain; Stryckmans, Pierre; Huez, Georges

doi:10.1182/blood.v76.11.2337.2337

Cited by 16 publications

(3 citation statements)

References 27 publications

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“…Although the number of cytogenetic responses observed in our patients is small, the data obtained clearly show that, in parallel to haematological responses, failure to achieve a cytogenetic response is not necessarily due to defects in IFN-alpha signalling. Two previous reports failed to demonstrate clear-cut correlations between the level of mRNA transcripts of IFN-dependent genes and the clinical outcome of IFN-alpha therapy in CML (Clauss et al, 1990;Talpaz et al, 1992). However, these studies did not 2 10 6 IU IFN-alpha 2b.…”

Section: Discussionmentioning

confidence: 96%

Induction of interferon regulatory factors, 2′‐5′ oligoadenylate synthetase, P68 kinase and RNase L in chronic myelogenous leukaemia cells and its relationship to clinical responsiveness

et al. 1996

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The genes crucially determining the therapeutic response of chronic myelogenous leukaemia (CML) to interferon-alpha (IFN-alpha) are unknown. Recently, two independent IFN-alpha signalling pathways were identified: the classic pathway mediates induction of 2'-5' oligoadenylate synthetase (2-5 OAS), p68 kinase and IFN regulatory factor-2 (IRF-2), whereas the alternate pathway leads to activation of IFN regulatory factor-1 (IRF-1). We investigated whether deficient or imbalanced expression of components of these two pathways is associated with resistance of CML cells to antiproliferative action of IFN alpha/beta. Constitutive and IFN-induced transcript levels of IFN-dependent genes in mononuclear cells, granulocytes, monocytes, lymphocytes and CD34+ cells of chronic-phase CML and blast crisis patients were assessed by Northern blot techniques and were correlated with subsequent clinical responses to IFN therapy. Our results demonstrated that IFN-alpha or -beta treatment in vitro and in vivo leads to an enhanced expression of IRF-1, IRF-2. RNase L, p68 and 2-5 OAS which was independent of the degree of cellular differentiation and clonal evolution of CML. Neither the magnitude of induction of these genes nor the IRF-1/IRF-2 mRNA balance differed between chronic-phase CML patients responding or failing IFN-alpha therapy. These results indicate that failure of IFN-alpha treatment is not due to defects in mRNA induction of the above-mentioned candidate genes for the direct antiproliferative response to IFN type I.

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Section: Discussionmentioning

confidence: 96%

Induction of interferon regulatory factors, 2′‐5′ oligoadenylate synthetase, P68 kinase and RNase L in chronic myelogenous leukaemia cells and its relationship to clinical responsiveness

et al. 1996

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“…However, other independent markers or indicators for determining which patients should be treated with α‐IFN are not yet known. One possible marker is the induction of the expression of α‐IFN‐stimulated genes35; however, this association is still controversial 36, 37. The current study results indicate that CML patients with normal TRFs who are treated with α‐IFN have a low incidence of blast crisis and a favorable prognosis.…”

Section: Discussionmentioning

confidence: 99%

The relationship between telomere length and therapy-associated cytogenetic responses in patients with chronic myeloid leukemia

Iwama¹,

Ohyashiki²,

Ohyashiki³

et al. 1997

Cancer

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. matched normal range (mean { 2 1 standard deviation [SD]) and the remaining 2 Department of Cell Biology and Neuroscience, 25 patients had TRFs shorter than the age-matched normal range (õ mean { 2 1 The University of Texas Southwestern Medical SD). Hematologic findings, including leukocyte count, hemoglobin level, platelet Center, Dallas, Texas.count, and percentage of bone marrow blasts at the time of diagnosis did not significantly differ between patients with normal and shortened TRFs; however, those with shortened TRFs had high levels of telomerase activity (P Å 0.045). In a group of patients treated with alpha-interferon (n Å 32), those with normal TRFs had a significantly lower frequency of blast crises (P Å 0.0328), a significantly higher incidence of cytogenetic responses (P Å 0.0185), and a favorable prognosis (P õ 0.01) compared with those with shortened TRFs.CONCLUSIONS. These findings suggest that normal TRFs in a small number of CML patients at the time of diagnosis may have a significant amount of normal stem cells remaining. The authors suggest that normal TRFs at the time of diagnosis indicate a subset of CML patients who may respond favorably to alpha-interferon therapy.

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“…12 ' 13) The therapeutic mechanism of action of a-IFN has not yet been defined; some researchers have suggested that a-IFN may exert its inhibitory effect on leukemic cells indirectly by acting on other cells and that resistance to a-IFN treatment could be due to lack of sensitivity of these cells to a-IFN. 14) In an attempt to determine the clinical implications of ISG expression in CML patients, we studied ISG expression in such patients to determine whether the anti-proliferative effect of a-IFN and ISG expression may be related to their hematologic and cytogenetic responses.…”

Section: Introductionmentioning

confidence: 99%

A Possible Correlation between Interferon-stimulated Gene Expression and Cytogenetic Responses in Chronic Myelogenous Leukemia Patients Treated with -interferon

Kawakubo¹,

Ohyashiki²,

Ohyashiki³

et al. 1996

Japanese Journal of Clinical Oncology

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We studied the expression of the interferon-stimulated genes (ISGs), ISG-54 and 2',5'-oligoadenylate synthetase (2'-5' OAS), using the reverse transcription-polymerase chain reaction in 22 patients with chronic myelogenous leukemia (CML), who were treated with alpha-interferon (alpha-IFN). At the time of diagnosis, 7 patients (31.8%) showed no detectable expression of either gene, whereas 8 expressed both. The remaining 7 expressed neither ISG-54 nor 2'-5' OAS. After alpha-IFN treatment, 5 of the 7 CML patients who had not previously express ISGs expressed either ISG-54 or 2'5' OAS or both and 6 of the 7 who had previously expressed either ISG-54 or 2'-5' OAS expressed both. Three of the 7 (42.9%) CML patients who expressed both genes before and after alpha-IFN administration showed cytogenetic responses, as did 6 of the 11 (54.5%) in whom ISG expression was induced. In contrast, cytogenetic responses occurred in none of the patients in whom ISG expression was not induced. These results suggest that induction of ISG-54 and 2'-5' OAS expression by alpha-IFN may be an indicator of cytogenetic responses and, therefore, of value for monitoring CML patients.

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Analysis of interferon-inducible genes in cells of chronic myeloid leukemia patients responsive or resistant to an interferon-alpha treatment

Cited by 16 publications

References 27 publications

Induction of interferon regulatory factors, 2′‐5′ oligoadenylate synthetase, P68 kinase and RNase L in chronic myelogenous leukaemia cells and its relationship to clinical responsiveness

Induction of interferon regulatory factors, 2′‐5′ oligoadenylate synthetase, P68 kinase and RNase L in chronic myelogenous leukaemia cells and its relationship to clinical responsiveness

The relationship between telomere length and therapy-associated cytogenetic responses in patients with chronic myeloid leukemia

A Possible Correlation between Interferon-stimulated Gene Expression and Cytogenetic Responses in Chronic Myelogenous Leukemia Patients Treated with -interferon

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