Abstract/Details

A role for Myb in BCR-ABL(p190)-induced leukemogenesis: Regulation of Arf suppression through transcriptional activation of BMI1


2010 2010

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Abstract (summary)

Philadelphia chromosome positive acute lymphoblastic leukemia (Ph +-ALL), carrying the e1a2 fusion BCR-ABL oncogene, is typically an aggressive B cell leukemia, often resistant to current treatment options. The transcription factor MYB plays a critical role in B cell development, but its role in B cell leukemia is unknown. To study the role of MYB in BCR-ABL-induced lymphoblastic leukemia, we compared disease induction, latency and survival in mice injected with BCR-ABLp190-transduced Myb+/- bone marrow and mice expressing the BCR-ABLp190 transgene in a Myb+/- background. Recipients of BCR-ABL-transduced Myb +/- bone marrow and transgenic BCR-ABL+Myb +/- mice showed a distinct leukemia-resistant phenotype, whereas, recipients of BCR-ABL-transduced Myb +/+ bone marrow and transgenic BCR-ABL+Myb +/+ mice exhibited rapid induction of B-ALL with shortened survival. Overexpression of a constitutively active form of MYB, Δ(358-452)MYB, rescued the pre-B cell colony formation of BCR-ABL +Myb+/- bone marrow. Using microarray analysis to examine differential gene expression, we identified the polycomb gene, Bmi1, as a putative downstream target of Myb in BCR-ABL p190-expressing murine pre-B cells. Bmi1 knockdown reduced pre-B colony formation of BCR-ABL+—Myb+/+ bone marrow; conversely, Bmi1 overexpression rescued colony formation of BCR-ABL+Myb+/- bone marrow. We have demonstrated that BMI1 is a direct target of MYB transactivation through the use of ChIP and luciferase assays. Consistent with its described role as a target of Bmi1-mediated suppression, p19Arf expression increased in BCR-ABL+Myb +/- pre-B cells. Knockdown of p19Arf led to a rescue of primary, but not secondary, pre-B cell colony formation of BCR-ABL +Myb+/- bone marrow, suggesting that modulation of other Myb and Bmi1 targets is necessary for leukemogenesis. Finally, we used knockdown of MYB and BMI1 in Ph+ALL cell lines to demonstrate the significant role of each in human disease. Altogether, our data suggest that induction of ALL by BCR-ABLp190 requires Myb-mediated activation of Bmi1 and subsequent silencing of Arf expression.

Indexing (details)


Subject
Genetics;
Oncology
Classification
0369: Genetics
0992: Oncology
Identifier / keyword
Health and environmental sciences, Biological sciences, Acute lymphoblastic leukemia, B cell leukemia, BCR/ABL, Cancer, Leukemia
Title
A role for Myb in BCR-ABL(p190)-induced leukemogenesis: Regulation of Arf suppression through transcriptional activation of BMI1
Author
Waldron, Todd J.
Number of pages
209
Publication year
2010
Degree date
2010
School code
0272
Source
DAI-B 72/01, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9781124378114
Advisor
Calabretta, Bruno
Committee member
Buchberg, Arthur; Manser, Timothy; McMahon, Steven
University/institution
Thomas Jefferson University
Department
Genetics
University location
United States -- Pennsylvania
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3432795
ProQuest document ID
818344421
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/818344421
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