Expression of interferon-alpha (IFN-alpha) receptor 2c at diagnosis is associated with cytogenetic response in IFN-alpha-treated chronic myeloid leukemia.

For the management of chronic myeloid leukemia (CML), prediction or early determination of the response to interferon-alpha (IFN-alpha) treatment is important for identifying nonresponder patients to whom alternative therapy may be proposed. In this study, the levels of expression of both BCR-ABL and subunit 2c of IFN-alpha receptor (IFN-alphaR2c) genes were analyzed at diagnosis in 74 patients with chronic phase CML treated with an IFN-alpha monotherapy. By using blood samples, real-time quantitative polymerase chain reaction was performed to quantify BCR-ABL, IFN-alphaR2c, and G6PDH mRNA as external control. The results were compared with hematologic and cytogenetic responses to IFN-alpha. A wide variation in the BCR-ABL/G6PDH ratio was observed at diagnosis (median, 6.68%; range, 0.18%-41.31%), but no significant association with response to IFN-alpha was observed. In contrast, the variation of IFN-alphaR2c/G6PDH ratio at diagnosis was significantly associated with the achievement of major cytogenetic response (MCR; 34% or lower Ph(+) metaphases). Median values of IFN-alphaR2c/G6PDH ratio for patients achieving MCR and for those who did not achieve it were 110.75% (range, 9.47%-612.30%) and 64.42% (range, 5.96%-425.40%), respectively (P =.037). In addition, this novel molecular factor, combined with the achievement of complete hematologic response at 3 months, makes it possible to predict MCR achievement with high probability by Kaplan-Meier analysis (91% +/- 17% at 24 months; P =.0001). (Blood. 2001;97:3568-3573)

[1]  M. Schmidt,et al.  Expression of interferon regulatory factor 4 in chronic myeloid leukemia: correlation with response to interferon alfa therapy. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  J. Melo,et al.  Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance. , 2000, Blood.

[3]  N. Cross,et al.  Detection and quantification of residual disease in chronic myelogenous leukemia , 2000, Leukemia.

[4]  T. Brümmendorf,et al.  Prognostic implications of differences in telomere length between normal and malignant cells from patients with chronic myeloid leukemia measured by flow cytometry. , 2000, Blood.

[5]  Branford,et al.  Monitoring chronic myeloid leukaemia therapy by real‐time quantitative PCR in blood is a reliable alternative to bone marrow cytogenetics , 1999, British journal of haematology.

[6]  A. Reiter,et al.  Accurate and rapid analysis of residual disease in patients with CML using specific fluorescent hybridization probes for real time quantitative RT-PCR , 1999, Leukemia.

[7]  A. D. de Vos,et al.  Determination of residues involved in ligand binding and signal transmission in the human IFN-alpha receptor 2. , 1999, Journal of immunology.

[8]  F. Révillion,et al.  Detection of BCR-ABL transcripts in chronic myeloid leukemia (CML) using a ‘real time’ quantitative RT-PCR assay , 1999, Leukemia.

[9]  P. Cony-Makhoul,et al.  Response at three months is a good predictive factor for newly diagnosed chronic myeloid leukemia patients treated by recombinant interferon-alpha. , 1998, Blood.

[10]  P. Cony-Makhoul,et al.  Response at Three Months Is a Good Predictive Factor for Newly Diagnosed Chronic Myeloid Leukemia Patients Treated by Recombinant Interferon-Presented in part at the 38th annual meeting of the American Society of Hematology, Orlando, FL, December 6-10, 1996. , 1998 .

[11]  H. Sekihara,et al.  Expression of interferon receptor genes (IFNAR1 and IFNAR2 mRNA) in the liver may predict outcome after interferon therapy in patients with chronic genotype 2a or 2b hepatitis C virus infection. , 1998, Journal of clinical gastroenterology.

[12]  M. Gordon,et al.  Expression of interferon regulatory factor (IRF) genes and response to interferon-α in chronic myeloid leukaemia , 1997, Leukemia.

[13]  H. Yatsuhashi,et al.  Quantitative analysis of interferon α/β receptor mRNA in the liver of patients with chronic hepatitis C: Correlation with serum hepatitis C virus‐RNA levels and response to treatment with interferon , 1997, Journal of gastroenterology and hepatology.

[14]  H. Mohri,et al.  Upregulation of interferon-alpha receptor expression in hydroxyurea-treated leukemia cell lines. , 1997, Journal of investigative medicine : the official publication of the American Federation for Clinical Research.

[15]  H. Heimpel,et al.  Molecular response of CML patients treated with interferon-alpha monitored by quantitative Southern blot analysis. German chronic myeloid leukaemia (CML) Study Group. , 1997, British journal of haematology.

[16]  J. Melo,et al.  The diversity of BCR-ABL fusion proteins and their relationship to leukemia phenotype. , 1996, Blood.

[17]  J. Goldman,et al.  Quantification of residual disease in chronic myelogenous leukemia patients on interferon-alpha therapy by competitive polymerase chain reaction. , 1996, Blood.

[18]  T. Lion,et al.  Increase of bcr-abl chimeric mRNA expression in tumor cells of patients with chronic myeloid leukemia precedes disease progression. , 1995, Blood.

[19]  O. Colamonici,et al.  Cloning and Expression of a Long Form of the β Subunit of the Interferon αβ Receptor That Is Required for Signaling (*) , 1995, The Journal of Biological Chemistry.

[20]  J. Halsey,et al.  Analysis of molecular breakpoint and m‐RNA transcripts in a prospective randomized trial of interferon in chronic myeloid leukaemia: no correlation with clinical features, cytogenetic response, duration of chronic phase, or survival , 1995, British journal of haematology.

[21]  H. Kantarjian,et al.  Prolonged Survival in Chronic Myelogenous Leukemia after Cytogenetic Response to Interferon- Therapy , 1995, Annals of Internal Medicine.

[22]  B. Cohen,et al.  The human interferon α β receptor: Characterization and molecular cloning , 1994, Cell.

[23]  S. Constantinescu,et al.  Complementation of the interferon alpha response in resistant cells by expression of the cloned subunit of the interferon alpha receptor. A central role of this subunit in interferon alpha signaling. , 1994, The Journal of biological chemistry.

[24]  Sante Tura,et al.  Interferon alfa-2a as compared with conventional chemotherapy for the treatment of chronic myeloid leukemia. , 1994, The New England journal of medicine.

[25]  J. Tanzer,et al.  Quantitative determination of the hybrid Bcr‐Abl RNA in patients with chronic myelogenous leukaemia under interferon therapy , 1992, British journal of haematology.

[26]  L. Platanias,et al.  Expression of the IFNα receptor in hairy cell leukaemia , 1992 .

[27]  G. Daley,et al.  Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. , 1990, Science.

[28]  G. Lutfalla,et al.  Genetic transfer of a functional human interferon α receptor into mouse cells: Cloning and expression of its c-DNA , 1990, Cell.

[29]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[30]  J. Gutterman,et al.  Chronic myelogenous leukaemia: haematological remissions with alpha interferon , 1986, British journal of haematology.

[31]  H. Kantarjian,et al.  Hematologic remission and cytogenetic improvement induced by recombinant human interferon alpha A in chronic myelogenous leukemia. , 1986, The New England journal of medicine.

[32]  E. Canaani,et al.  Fused transcript of abl and bcr genes in chronic myelogenous leukaemia , 1985, Nature.

[33]  Francisco Cervantes,et al.  Prognostic discrimination in "good-risk" chronic granulocytic leukemia , 1984 .

[34]  T. Papayannopoulou,et al.  Chronic myelocytic leukemia: clonal origin in a stem cell common to the granulocyte, erythrocyte, platelet and monocyte/macrophage. , 1977, The American journal of medicine.

[35]  G. Canellos,et al.  Chronic granulocytic leukemia. , 1976, The Medical clinics of North America.

[36]  J. M. Buchanan,et al.  The wolf in the cello , 1973 .

[37]  E. Kaplan,et al.  Nonparametric Estimation from Incomplete Observations , 1958 .

[38]  J. Waring,et al.  Lack of Interferon Consensus Sequence Binding Protein (ICSBP) Transcripts in Human Myeloid Leukemias , 1998 .

[39]  G. Martinelli,et al.  Detection of bcr-abl transcript in chronic myelogenous leukemia patients by reverse-transcription-polymerase chain reaction and capillary electrophoresis. , 1998, Haematologica.

[40]  D. H. Mellor,et al.  Real time , 1981 .

[41]  P. Nowell,et al.  A minute chromosome in human chronic granulocytic leukemia , 1960 .