A SALL4/MLL/HOXA9 pathway in murine and human myeloid leukemogenesis.
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.
Ailing
A
Li
Youyang
Y
Yang
Chong
C
Gao
Jiayun
J
Lu
Ha-Won
HW
Jeong
Bee H
BH
Liu
Ping
P
Tang
Xiaopan
X
Yao
Donna
D
Neuberg
Gang
G
Huang
Daniel G
DG
Tenen
Li
L
Chai
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D063646:Carcinogenesis / Q000378:metabolism*; D015870:Gene Expression; D015973:Gene Expression Regulation, Leukemic; D057809:HEK293 Cells; D006412:Hematopoietic Stem Cells; D011495:Histone-Lysine N-Methyltransferase; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism*; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D018398:Homeodomain Proteins; C497422:KMT2A protein, human; D020033:Protein Isoforms; C472575:SALL4 protein, human; D014157:Transcription Factors; C097899:homeobox protein HOXA9; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase