Expression of interferon regulatory factor 4 in chronic myeloid leukemia: correlation with response to interferon alfa therapy.
OBJECTIVE
Mice experiments have established an important role for interferon regulatory factor (IRF) family members in hematopoiesis. We wanted to study the expression of interferon regulatory factor 4 (IRF4) in various hematologic disorders, especially chronic myeloid leukemia (CML), and its association with response to interferon alfa (IFN-alpha) treatment in CML.


METHODS
Blood samples from various hematopoietic cell lines, different leukemia patients (70 CML, 29 acute myeloid leukemia [AML], 10 chronic myelomonocytic leukemia [CMMoL], 10 acute lymphoblastic leukemia, and 10 chronic lymphoid leukemia patients), and 33 healthy volunteers were monitored for IRF4 expression by reverse transcriptase polymerase chain reaction. Then, with a focus on CML, the IRF4 level was determined in sorted cell subpopulations from CML patients and healthy volunteers and in in vitro-stimulated CML cells. Furthermore, IRF4 expression was compared in the CML samples taken before IFN-alpha therapy and in 47 additional CML samples taken during IFN-alpha therapy. IRF4 expression was then correlated with cytogenetic response to IFN-alpha.


RESULTS
IRF4 expression was significantly impaired in CML, AML, and CMMoL samples. The downregulation of IRF4 in CML samples was predominantly found in T cells. In CML patients during IFN-alpha therapy, a significant increase in IRF4 levels was detected, and this was also observed in sorted T cells from CML patients. The increase seen during IFN-alpha therapy was not due to different blood counts. In regard to the cytogenetic response with IFN-alpha, a good response was associated with high IRF4 expression.


CONCLUSIONS
IRF4 expression is downregulated in T cells of CML patients, and its increase is associated with a good response to IFN-alpha therapy. These data suggest IRF4 expression as a useful marker to monitor, if not predict, response to IFN-alpha in CML.
Schmidt
M
M
Zentrum für Innere Medizin, Abteilung Hämatologie/Onkologie/Immunologie, Klinikum der Philipps-Universität Marburg, Marburg.
Hochhaus
A
A
König-Merediz
S A
SA
Brendel
C
C
Proba
J
J
Hoppe
G J
GJ
Wittig
B
B
Ehninger
G
G
Hehlmann
R
R
Neubauer
A
A
D000208:Acute Disease; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D002986:Clinical Trials as Topic; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D006801:Humans; D050835:Interferon Regulatory Factors; D016898:Interferon-alpha / Q000627:therapeutic use*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000188:drug therapy / Q000276:immunology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood* / Q000188:drug therapy* / Q000276:immunology; D007951:Leukemia, Myeloid / Q000097:blood / Q000188:drug therapy / Q000276:immunology; D015477:Leukemia, Myelomonocytic, Chronic / Q000097:blood / Q000188:drug therapy / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D016131:Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000188:drug therapy / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D014407:Tumor Cells, Cultured; D000099218:Interferon Regulatory Factor-4
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D050835:Interferon Regulatory Factors; D016898:Interferon-alpha; D012333:RNA, Messenger; D014157:Transcription Factors; D000099218:Interferon Regulatory Factor-4