In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 433-433
Kurzfassung:
Our goal is to identify oncogenic loci in regions of recurrent DNA copy number alterations in cancer. Constitutional trisomy 21 (Down syndrome) carries a 20-fold increased risk of B-ALL, and chr.21 gains are the most common acquired aneuploidy in B-ALL. Interstitial amplification in the chr.21q22 region (iAMP21) is also a recurrent finding in B-ALL and carries a poor prognosis. However, the gene(s) on chr.21 responsible for this association remain unclear. We studied the Ts1Rhr mouse, which carries germline triplication of 31 genes homologous to human chr.21q22. Chr.21q22 triplication was sufficient to promote B cell autonomous self-renewal and maturation defects, and cooperated with BCR-ABL or CRLF2 with JAK2 R683G to accelerate leukemogenesis. Chr.21q22 triplication also resulted in histone H3K27 hypomethylation at gene promoters, and the expression signature of triplicated B cells was enriched for genes targeted by polycomb repressor complex 2 (PRC2), which trimethylates H3K27. Thus, chr.21q22 triplication may deregulate B cell development by causing H3K27 hypomethylation at genes critical for progenitor cell growth. In support of this hypothesis, pharmacologic inhibition of PRC2 function was sufficient to confer self-renewal in wild-type B cells, while inhibition of H3K27 demethylases blocked self-renewal induced by chr.21q22 triplication. In three independent B-ALL cohorts, PRC2/H3K27 gene signatures distinguished leukemias with +21 from those without, validating the same biology in human disease. One of the 31 triplicated genes, HMGN1, encodes a nucleosome binding protein known to modulate chromatin structure and facilitate transcriptional activation. When we overexpressed HMGN1 in BaF3 proB cells, H3K27me3 decreased proportionally to the level of overexpression. We next knocked down each of the 31 triplicated genes with lentivirally-expressed shRNAs (5 per gene) and assessed the effects on growth of Ts1Rhr and wild-type primary B cells. Strikingly, Hmgn1 was the top scoring gene and all 5 hairpins targeting Hmgn1 were depleted in the assay. Finally, we studied transgenic mice (HMGN1_OE) that overexpress human HMGN1 (∼2-fold total overexpression). HMGN1_OE mice had a defect in B cell maturation, increased proB colony forming capacity, and a transcriptional signature overlapping with that of triplication of all 31 Ts1Rhr genes. In a bone marrow transplant model driven by BCR-ABL, recipients of HMGN1_OE bone marrow developed B-ALL with decreased latency (median 33 days vs not reached) and increased penetrance (17/18 vs 4/17 mice died by 80 days; leukemia-free survival difference P & lt;0.001) compared to recipients of wild-type bone marrow. These data indicate that HMGN1 is a B-ALL oncogene, and therapies targeting HMGN1 or the downstream effects of HMGN1 overexpression on epigenetic histone modifications may be effective in B-ALL with copy number gains involving chr.21q22. Citation Format: Andrew A. Lane, Bjoern Chapuy, Charles Y. Lin, Trevor Tivey, Hubo Li, Elizabeth Townsend, Diederik van Bodegom, Tovah A. Day, Shuo-Chieh Wu, Huiyun Liu, Akinori Yoda, Gabriela Alexe, Anna Schinzel, Timothy J. Sullivan, Sebastien Malinge, Jordan Taylor, Kimberly Stegmaier, Jacob Jaffe, Michael Bustin, Geertruy te Kronnie, Shai Izraeli, Marian Harris, Kristen Stevenson, Donna Neuberg, Lewis B. Silverman, Steven E. Sallan, James E. Bradner, William C. Hahn, John D. Crispino, David Pellman, David M. Weinstock. Triplication of HMGN1 promotes B cell acute lymphoblastic leukemia (B-ALL) through suppression of H3K27me3. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 433. doi:10.1158/1538-7445.AM2014-433
Materialart:
Online-Ressource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2014-433
Sprache:
Englisch
Verlag:
American Association for Cancer Research (AACR)
Publikationsdatum:
2014
ZDB Id:
2036785-5
ZDB Id:
1432-1
ZDB Id:
410466-3
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