SALL4, a novel oncogene, is constitutively expressed in human acute myeloid leukemia (AML) and induces AML in transgenic mice.
SALL4, a human homolog to Drosophila spalt, is a novel zinc finger transcriptional factor essential for development. We cloned SALL4 and its isoforms (SALL4A and SALL4B). Through immunohistochemistry and real-time reverse-transcription-polymerase chain reaction (RT-PCR), we demonstrated that SALL4 was constitutively expressed in human primary acute myeloid leukemia (AML, n = 81), and directly tested the leukemogenic potential of constitutive expression of SALL4 in a murine model. SALL4B transgenic mice developed myelodysplastic syndrome (MDS)-like features and subsequently AML that was transplantable. Increased apoptosis associated with dysmyelopoiesis was evident in transgenic mouse marrow and colony-formation (CFU) assays. Both isoforms could bind to beta-catenin and synergistically enhanced the Wnt/beta-catenin signaling pathway. Our data suggest that the constitutive expression of SALL4 causes MDS/AML, most likely through the Wnt/beta-catenin pathway. Our murine model provides a useful platform to study human MDS/AML transformation, as well as the Wnt/beta-catenin pathway's role in the pathogenesis of leukemia stem cells.
Ma
Yupo
Y
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
Cui
Wei
W
Yang
Jianchang
J
Qu
Jun
J
Di
Chunhui
C
Amin
Hesham M
HM
Lai
Raymond
R
Ritz
Jerome
J
Krause
Diane S
DS
Chai
Li
L
D017398:Alternative Splicing; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D003001:Cloning, Molecular; D003114:Colony-Forming Units Assay; D018076:DNA, Complementary / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D006410:Hematopoiesis; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009368:Neoplasm Transplantation; D009857:Oncogenes; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
D018076:DNA, Complementary; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C472575:SALL4 protein, human; C509167:Sall4 protein, mouse; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin