Mll partial tandem duplication induces aberrant Hox expression in vivo via specific epigenetic alterations.
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. Mll(PTD/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. Mll(PTD/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.
Dorrance
Adrienne M
AM
Department of Internal Medicine, Division of Hematology and Oncology, The Ohio State University, Columbus, Ohio 43220, USA.
Liu
Shujun
S
Yuan
Weifeng
W
Becknell
Brian
B
Arnoczky
Kristy J
KJ
Guimond
Martin
M
Strout
Matthew P
MP
Feng
Lan
L
Nakamura
Tatsuya
T
Yu
Li
L
Rush
Laura J
LJ
Weinstein
Michael
M
Leone
Gustavo
G
Wu
Lizhao
L
Ferketich
Amy
A
Whitman
Susan P
SP
Marcucci
Guido
G
Caligiuri
Michael A
MA
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics*; D020440:Gene Duplication; D015870:Gene Expression / Q000235:genetics*; D015321:Gene Rearrangement / Q000235:genetics; D005838:Genotype; D006410:Hematopoiesis / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000378:metabolism; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D012272:Ribs / Q000002:abnormalities / Q000378:metabolism; D020080:Tandem Repeat Sequences / Q000235:genetics*
D006657:Histones; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; C492047:Hoxa7 protein, mouse; D009363:Neoplasm Proteins; D051788:Myeloid-Lymphoid Leukemia Protein; C088144:HoxA protein; C092119:Hoxa10 protein, mouse; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse