B-cell activating factor and v-Myc myelocytomatosis viral oncogene homolog (c-Myc) influence progression of chronic lymphocytic leukemia

Weizhou Zhang; Arnon P Kater; George F Widhopf; Han-Yu Chuang; Thomas Enzler; Danelle F James; Maxim Poustovoitov; Ping-Hui Tseng; Siegfried Janz; Carl Hoh; Harvey Herschman; Michael Karin; Thomas J Kipps

doi:10.1073/pnas.1013420107

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B-cell activating factor and v-Myc myelocytomatosis viral oncogene homolog (c-Myc) influence progression of chronic lymphocytic leukemia

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B-cell activating factor and v-Myc myelocytomatosis viral oncogene homolog (c-Myc) influence progression of chronic lymphocytic leukemia

Weizhou Zhang, Arnon P Kater, George F Widhopf, Han-Yu Chuang, Thomas Enzler, Danelle F James, Maxim Poustovoitov, Ping-Hui Tseng, Siegfried Janz, Carl Hoh, …

Proceedings of the National Academy of Sciences - PNAS, Vol.107(44), pp.18956-18960

11/02/2010

DOI: 10.1073/pnas.1013420107

PMCID: PMC2973856

PMID: 20956327

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Abstract

Mice bearing a v-Myc myelocytomatosis viral oncogene homolog (c-Myc) transgene controlled by an Ig-alpha heavy-chain enhancer (iMycCα mice) rarely develop lymphomas but instead have increased rates of memory B-cell turnover and impaired antibody responses to antigen. We found that male progeny of iMycCα mice mated with mice transgenic (Tg) for CD257 (B-cell activating factor, BAFF) developed CD5+ B-cell leukemia resembling human chronic lymphocytic leukemia (CLL), which also displays a male gender bias. Surprisingly, leukemic cells of Myc/Baff Tg mice expressed higher levels of c-Myc than did B cells of iMycCα mice. We found that CLL cells of many patients with progressive disease also expressed high amounts of c-MYC, particularly CLL cells whose survival depends on nurse-like cells (NLC), which express high-levels of BAFF. We find that BAFF could enhance CLL-cell expression of c-MYC via activation the canonical IκB kinase (IKK)/NF-κB pathway. Inhibition of the IKK/NF-κB pathway in mouse or human leukemia cells blocked the capacity of BAFF to induce c-MYC or promote leukemia-cell survival and significantly impaired disease progression in Myc/Baff Tg mice. This study reveals an important relationship between BAFF and c-MYC in CLL which may affect disease development and progression, and suggests that inhibitors of the canonical NF-κB pathway may be effective in treatment of patients with this disease.

Biological Sciences

leukemia-cell survival

prognostic factors

nuclear factor κ-light-chain enhancer of activated B cells, IκB kinase inhibitor

nurselike cells

Details

Title: Subtitle: B-cell activating factor and v-Myc myelocytomatosis viral oncogene homolog (c-Myc) influence progression of chronic lymphocytic leukemia
Creators: Weizhou Zhang - Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine and
Arnon P Kater - Department of Hematology
George F Widhopf - Departments of
Han-Yu Chuang - Departments of
Thomas Enzler - Department of Medicine
Danelle F James - Departments of
Maxim Poustovoitov - Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine and
Ping-Hui Tseng - Institute of Biochemistry and Molecular Biology
Siegfried Janz - Department of Pathology
Carl Hoh - Radiology, Moores Cancer Center
Harvey Herschman - Departments of
Michael Karin - Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine and
Thomas J Kipps - Departments of
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.107(44), pp.18956-18960
DOI: 10.1073/pnas.1013420107
PMID: 20956327
PMCID: PMC2973856
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences
Language: English
Date published: 11/02/2010
Academic Unit: Pathology; Radiation Oncology
Record Identifier: 9984083874902771

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