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?Investigating Chromatin States in HOX-induced AML
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By CourteneyLai, Section Biology
Posted on Fri Apr 30th, 2010 at 01:40:28 PM PST
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Acute myeloid leukemia (AML) is a subcategory of leukemias targeting the myeloid lineage of blood cell development characterised by abnormal accumulation of white blood cells in the bone marrow. This disease, though rare in the general population, is the most common type of leukemia among older adults. HOX genes have been directly linked to leukemia, notably through translocations between Abd-B HOX genes and the nucleoporin gene NUP98 in human leukemias.[1, 2]
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Direct involvement of NUP98-HOX fusion genes in the development of has been demonstrated in the mouse bone marrow model where retroviral overexpression of NUP98-HOXA9 or NUP98-HOXD13 gave rise to AML. [3, 4] Interestingly, however, an engineered NUP98-HOXA10 fusion can induce cell expansion, especially at the hematopoietic stem cell level, but mice transplanted with this fusion fail to progress to AML. [5]
It has been previously observed that embryonic cells tend to exist in a bivalent or plastic chromatin state, with ES cells exhibiting a combination of both active (dimethylated H3K4) and suppressing (trimethylated H3K27) histone marks until they mature into fibroblasts.[6] In addition, embryonic carcinoma cells acquire additional both tri- and dimethylated marks at H3K9, both of which are associated with DNA hypermethylation seen in adult cancers.[7-9] This indicates that H3K9 methylation may be an important biomarker for DNA methylation and subsequent cancer development. Therefore, I propose to investigate the existence of bivalent chromatin states in adult bone marrow cells and to compare and contrast chromatin patterns in non-malignant compared to tumour-initiated cells. ChIP-Seq will be done on mouse bone marrow cells that have been retrovirally transduced with AML-initiating (NUP98-HOXA9, NUP98-HOXD13) or non-initiating (NUP98-HOXA10) plasmids. The chromatin patterns of these cells will be examined, paying particular attention to H3K4, H3K27, and H3K9 methylation patterns. In the non-leukemic cells (NUP98-HOXA10), I would expect to see genes with active chromatin marks (H3K4 methylation), repressed chromatin marks (H3K27 methylation), and genes in a bivalent state (H3K4 and H3K27 methylation). In cells with tumour-initiating potential (NUP98-HOXA9 and NUP98-HOXD13), I would expect to see some genes that were previously H3K4 or H3K27 methylated only showing lower levels of activation, increased H3K9 methylation, and genes that were previously in a bivalent chromatin state showing higher levels of either activation or repression. This would provide evidence for H3K9 di- and trimethylation as a precursor histone modification for the development of cancer, as well as indicate candidate genes that may be responsible for initiating malignant cellular machinery.
REFERENCES
1. Slape, C. and P.D. Aplan, The role of NUP98 gene fusions in hematologic malignancy. Leuk Lymphoma, 2004. 45(7): p. 1341-50.
2. Nakamura, T., NUP98 fusion in human leukemia: dysregulation of the nuclear pore and homeodomain proteins. Int J Hematol, 2005. 82(1): p. 21-7.
3. Kroon, E., et al., NUP98-HOXA9 expression in hemopoietic stem cells induces chronic and acute myeloid leukemias in mice. EMBO J, 2001. 20(3): p. 350-61.
4. Pineault, N., et al., Induction of acute myeloid leukemia in mice by the human leukemia-specific fusion gene NUP98-HOXD13 in concert with Meis1. Blood, 2003. 101(11): p. 4529-38.
5. Pineault, N., et al., Differential and common leukemogenic potentials of multiple NUP98-Hox fusion proteins alone or with Meis1. Mol Cell Biol, 2004. 24(5): p. 1907-17.
6. Azuara, V., et al., Chromatin signatures of pluripotent cell lines. Nat Cell Biol, 2006. 8(5): p. 532-8.
7. McGarvey, K.M., et al., Silenced tumor suppressor genes reactivated by DNA demethylation do not return to a fully euchromatic chromatin state. Cancer Res, 2006. 66(7): p. 3541-9.
8. Kondo, Y., L. Shen, and J.P. Issa, Critical role of histone methylation in tumor suppressor gene silencing in colorectal cancer. Mol Cell Biol, 2003. 23(1): p. 206-15.
9. Nguyen, C.T., et al., Histone H3-lysine 9 methylation is associated with aberrant gene silencing in cancer cells and is rapidly reversed by 5-aza-2'-deoxycytidine. Cancer Res, 2002. 62(22): p. 6456-61. |
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