MUM1/IRF4 expression in the circulating compartment of chronic lymphocytic leukemia

MUM1/IRF4 is normally expressed in late germinal center/post germinal center B-cells. Previous studies of chronic lymphocytic leukemia in bone marrow and lymph node have demonstrated variable expression of MUM1/IRF4 and conflicting prognostic significance. In this study we evaluated MUM1/IRF4 expression in peripheral blood CLL cells utilizing Histogel™ cell blocks. MUM1/IRF4 was absent in 4/36 (11%) specimens. The remaining cases demonstrated variable intensity and proportion of positive cells: <20% positive 16/36 (44%), 20 – 50% positive 12/36 (33%), >50% 4/36 (11%). No correlation was identified between MUM1/IRF4 and percent of CD38 positive cells, CD38 status (+/−), ZAP-70 status (+/−), and IgVH mutational status. The variability in MUM1/IRF4 staining suggests a level of biologic complexity that is not adequately reflected in the current binary models of CLL pathobiology. This heterogeneity may reflect the role of MUM1/IRF4 as an effector and integrator of several lymphocyte activation pathways including antigenic and environmental stimuli.

[1]  N. Chiorazzi,et al.  CD38 Expression Identifies an Active Subset of Proliferating Cells within the Clonal Population in Chronic Lymphocytic Leukemia Patients (In Vitro Analysis). , 2006 .

[2]  Qiong Shen,et al.  Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination , 2006, Nature Immunology.

[3]  S. Swerdlow,et al.  The proliferation center microenvironment and prognostic markers in chronic lymphocytic leukemia/small lymphocytic lymphoma. , 2006, Human pathology.

[4]  S. Iida,et al.  Multiple myeloma oncogene 1 (MUM1)/interferon regulatory factor 4 (IRF4) upregulates monokine induced by interferon-γ (MIG) gene expression in B-cell malignancy , 2005, Leukemia.

[5]  L. Klein-Hitpass,et al.  Combined analysis of ZAP-70 and CD38 expression as a predictor of disease progression in B-cell chronic lymphocytic leukemia , 2005, Leukemia.

[6]  L. Rassenti,et al.  ZAP-70 directly enhances IgM signaling in chronic lymphocytic leukemia. , 2005, Blood.

[7]  K. Foon,et al.  Immunoglobulin Heavy Chain (IgH) Gene Somatic Hypermutation Status Using Homoduplex-Separated RT-PCR Products. , 2004 .

[8]  Arthur Weiss,et al.  ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. , 2004, The New England journal of medicine.

[9]  N. Chiorazzi,et al.  Recent advances in the molecular biology and immunobiology of chronic lymphocytic leukemia. , 2004, Seminars in hematology.

[10]  F. Stevenson,et al.  Chronic lymphocytic leukemia: revelations from the B-cell receptor. , 2004, Blood.

[11]  Adrian Wiestner,et al.  ZAP-70 expression and prognosis in chronic lymphocytic leukaemia , 2004, The Lancet.

[12]  L. Staudt,et al.  Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. , 2004, Blood.

[13]  S. Deaglio,et al.  CD38 is a signaling molecule in B-cell chronic lymphocytic leukemia cells. , 2003, Blood.

[14]  Adrian Wiestner,et al.  ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile. , 2003, Blood.

[15]  Emili Montserrat,et al.  ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. , 2003, The New England journal of medicine.

[16]  G. Guida,et al.  The pattern of CD38 expression defines a distinct subset of chronic lymphocytic leukemia (CLL) patients at risk of disease progression. , 2003, Blood.

[17]  C. Chang,et al.  Expression of MUM1/IRF4 correlates with clinical outcome in patients with B-cell chronic lymphocytic leukemia. , 2002, Blood.

[18]  Axel Benner,et al.  Stromal-derived factor 1 inhibits the cycling of very primitive human hematopoietic cells in vitro and in NOD/SCID mice. , 2002, Blood.

[19]  M. Seto,et al.  MUM1/IRF4 Expression Is an Unfavorable Prognostic Factor in B‐Cell Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) , 2002, Japanese journal of cancer research : Gann.

[20]  T. Hamblin.  Chronic lymphocytic leukaemia: one disease or two? , 2002, Annals of Hematology.

[21]  D. Oscier,et al.  CD38 expression and immunoglobulin variable region mutations are independent prognostic variables in chronic lymphocytic leukemia, but CD38 expression may vary during the course of the disease. , 2002, Blood.

[22]  R. Bataille,et al.  CD38 expression and secondary 17p deletion are important 
prognostic factors in chronic lymphocytic leukaemia , 2002, British journal of haematology.

[23]  A. Pernis.  The role of IRF-4 in B and T cell activation and differentiation. , 2002, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[24]  K. Do,et al.  CD38 expression as an important prognostic factor in B-cell chronic lymphocytic leukemia. , 2001, Blood.

[25]  G. Ghandour,et al.  B‐lymphocyte quiescence, tolerance and activation as viewed by global gene expression profiling on microarrays , 2000, Immunological reviews.

[26]  H Stein,et al.  A monoclonal antibody (MUM1p) detects expression of the MUM1/IRF4 protein in a subset of germinal center B cells, plasma cells, and activated T cells. , 2000, Blood.

[27]  S. Swerdlow,et al.  Classification of small B-cell lymphoid neoplasms using a paraffin section immunohistochemical panel. , 2000, Applied immunohistochemistry & molecular morphology : AIMM.

[28]  I. Hanamura,et al.  MUM1/IRF4 expression as a frequent event in mature lymphoid malignancies , 2000, Leukemia.

[29]  Ash A. Alizadeh,et al.  Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling , 2000, Nature.

[30]  D. Dorfman,et al.  The chemokine receptor CXCR3 is expressed in a subset of B-cell lymphomas and is a marker of B-cell chronic lymphocytic leukemia. , 2000, Blood.

[31]  Sanjay Gupta,et al.  Lineage-Specific Modulation of Interleukin 4 Signaling by Interferon Regulatory Factor 4 , 1999, The Journal of experimental medicine.

[32]  R. Rosenquist,et al.  Clonal rearrangements in childhood and adult precursor B acute lymphoblastic leukemia: a comparative polymerase chain reaction study using multiple sets of primers , 1999, European journal of haematology.

[33]  N. Chiorazzi,et al.  Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. , 1999, Blood.