Intrinsic inhibition of transcription factor E2A by HLH proteins ABF-1 and Id2 mediates reprogramming of neoplastic B cells in Hodgkin lymphoma.
B cell differentiation is controlled by a complex network of lineage-restricted transcription factors. How perturbations to this network alter B cell fate remains poorly understood. Here we show that classical Hodgkin lymphoma tumor cells, which originate from mature B cells, have lost the B cell phenotype as a result of aberrant expression of transcriptional regulators. The B cell-specific transcription factor program was disrupted by overexpression of the helix-loop-helix proteins ABF-1 and Id2. Both factors antagonized the function of the B cell-determining transcription factor E2A. As a result, expression of genes specific to B cells was lost and expression of genes not normally associated with the B lineage was upregulated. These data demonstrate the plasticity of mature human lymphoid cells and offer an explanation for the unique classical Hodgkin lymphoma phenotype.
Mathas
Stephan
S
Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany. smathas@mdc-berlin.de
Janz
Martin
M
Hummel
Franziska
F
Hummel
Michael
M
Wollert-Wulf
Brigitte
B
Lusatis
Simone
S
Anagnostopoulos
Ioannis
I
Lietz
Andreas
A
Sigvardsson
Mikael
M
Jundt
Franziska
F
Jöhrens
Korinna
K
Bommert
Kurt
K
Stein
Harald
H
Dörken
Bernd
B
D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D019281:Dimerization; D015870:Gene Expression; D006689:Hodgkin Disease / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051797:Inhibitor of Differentiation Protein 2 / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes; D051757:PAX5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D051797:Inhibitor of Differentiation Protein 2; D046912:Multiprotein Complexes; D051757:PAX5 Transcription Factor; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C497450:ID2 protein, human; C112467:MSC protein, human; C497281:PAX5 protein, human; C407909:TCF3 protein, human