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A SALL4/MLL/HOXA9 pathway in murine and human myeloid leukemogenesis
Ailing Li, … , Daniel G. Tenen, Li Chai
Ailing Li, … , Daniel G. Tenen, Li Chai
Published September 24, 2013
Citation Information: J Clin Invest. 2013;123(10):4195-4207. https://doi.org/10.1172/JCI62891.
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Research Article Oncology

A SALL4/MLL/HOXA9 pathway in murine and human myeloid leukemogenesis

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Abstract

The embryonic self-renewal factor SALL4 has been implicated in the development of human acute myeloid leukemia (AML). Transgenic mice expressing the human SALL4B allele develop AML, which indicates that this molecule contributes to leukemia development and maintenance. However, the underlying mechanism of SALL4-dependent AML progression is unknown. Using SALL4B transgenic mice, we observed that HoxA9 was significantly upregulated in SALL4B leukemic cells compared with wild-type controls. Downregulation of HoxA9 in SALL4B leukemic cells led to decreased replating capacity in vitro and delayed AML development in recipient mice. In primary human AML cells, downregulation of SALL4 led to decreased HOXA9 expression and enhanced apoptosis. We found that SALL4 bound a specific region of the HOXA9 promoter in leukemic cells. SALL4 overexpression led to enhanced binding of histone activation markers at the HOXA9 promoter region, as well as increased HOXA9 expression in these cells. Furthermore, we observed that SALL4 interacted with mixed-lineage leukemia (MLL) and co-occupied the HOXA9 promoter region with MLL in AML leukemic cells, which suggests that a SALL4/MLL pathway may control HOXA9 expression. In summary, our findings revealed a molecular mechanism for SALL4 function in leukemogenesis and suggest that targeting of the SALL4/MLL/HOXA9 pathway would be an innovative approach in treating AML.

Authors

Ailing Li, Youyang Yang, Chong Gao, Jiayun Lu, Ha-Won Jeong, Bee H. Liu, Ping Tang, Xiaopan Yao, Donna Neuberg, Gang Huang, Daniel G. Tenen, Li Chai

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Figure 1

Upregulation of HoxA9 in SALL4B leukemic cells.

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Upregulation of HoxA9 in SALL4B leukemic cells.
 
(A–H) Leukemia develop...
(A–H) Leukemia development in recipient mice. Images are from a representative recipient of a primary transplant. Leukocytosis was observed in the blood smears (A). Blasts were present in the peripheral blood (B), BM smear (C), lymph node (D), spleen (E and F), and liver (G and H). Original magnification, ×40 (A, E, and G), ×200 (D, F, and H), ×600 (B and C). (I) SALL4 expression was determined by IHC staining in SALL4B leukemic BM cells. Original magnification, ×600. (J) Validation of HOXA9 upregulation in SALL4B leukemic GMP population. qRT-PCR analysis of gene expression in SALL4B leukemic GMPs compared with control normal GMPs. Measurements were from 3 individual secondary transplanted recipients (n = 3), each performed in triplicate. *P < 0.05. (K) Flow analysis of donor cell subtype after secondary transplantation.
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