Mll partial tandem duplication induces aberrant Hox expression in vivo via specific epigenetic alterations
Adrienne M. Dorrance, … , Guido Marcucci, Michael A. Caligiuri
Adrienne M. Dorrance, … , Guido Marcucci, Michael A. Caligiuri
Published October 2, 2006
Citation Information: J Clin Invest. 2006;116(10):2707-2716. https://doi.org/10.1172/JCI25546.
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Mll partial tandem duplication induces aberrant Hox expression in vivo via specific epigenetic alterations

Abstract

We previously identified a rearrangement of mixed-lineage leukemia (MLL) gene (also known as ALL-1, HRX, and HTRX1), consisting of an in-frame partial tandem duplication (PTD) of exons 5 through 11 in the absence of a partner gene, occurring in approximately 4%–7% of patients with acute myeloid leukemia (AML) and normal cytogenetics, and associated with a poor prognosis. The mechanism by which the MLL PTD contributes to aberrant hematopoiesis and/or leukemia is unknown. To examine this, we generated a mouse knockin model in which exons 5 through 11 of the murine Mll gene were targeted to intron 4 of the endogenous Mll locus. MllPTD/WT mice exhibit an alteration in the boundaries of normal homeobox (Hox) gene expression during embryogenesis, resulting in axial skeletal defects and increased numbers of hematopoietic progenitor cells. MllPTD/WT mice overexpress Hoxa7, Hoxa9, and Hoxa10 in spleen, BM, and blood. An increase in histone H3/H4 acetylation and histone H3 lysine 4 (Lys4) methylation within the Hoxa7 and Hoxa9 promoters provides an epigenetic mechanism by which this overexpression occurs in vivo and an etiologic role for MLL PTD gain of function in the genesis of AML.

Authors

Adrienne M. Dorrance, Shujun Liu, Weifeng Yuan, Brian Becknell, Kristy J. Arnoczky, Martin Guimond, Matthew P. Strout, Lan Feng, Tatsuya Nakamura, Li Yu, Laura J. Rush, Michael Weinstein, Gustavo Leone, Lizhao Wu, Amy Ferketich, Susan P. Whitman, Guido Marcucci, Michael A. Caligiuri

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Figure 2

Germline transmission and verification of correct targeting in mice heterozygous for the Mll PTD.

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Germline transmission and verification of correct targeting in mice hete...
(A) Southern blot analysis using high molecular-weight DNA from spleens, digested with NdeI and hybridized to a probe that spans intron 4 and exon 5 of Mll (i4e5 in Figure 1). This generates a single WT band at 18 kb in MllWT/WT mice, 2 bands representing 1 WT allele at 18 kb, and a band at 40 kb representing the rearranged allele in MllPTD/WT mice. (B) The Mll PTD fusion transcript was amplified using an upstream primer from Mll exon 11 and a downstream primer from Mll exon 6 amplifying a single 335-bp unique fusion transcript in the MllPTD/WT mouse (+) and is absent in the sample from the MllWT/WT mouse (–). Sequencing of these PCR products from the MllPTD/WT mice verified the presence of the exon 11–exon 5 fusion site. The 1-kb+ ladder was used to determine amplification size.