SALL4, a novel oncogene, is constitutively expressed in human acute myeloid leukemia (AML) and induces AML in transgenic mice

• Published in: Blood 2006-10, Vol.108 (8), p.2726-2735
• Main Authors: Ma, Yupo, Cui, Wei, Yang, Jianchang, Qu, Jun, Di, Chunhui, Amin, Hesham M., Lai, Raymond, Ritz, Jerome, Krause, Diane S., Chai, Li
• Format: Article
• Language: English
• Subjects: Alternative Splicing; Animals; Apoptosis; Base Sequence; beta Catenin - metabolism; Biological and medical sciences; Cloning, Molecular; Colony-Forming Units Assay; DNA, Complementary - genetics; DNA, Neoplasm - genetics; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Gene Expression; Hematologic and hematopoietic diseases; Hematopoiesis; Humans; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Mice; Mice, Transgenic; Myelodysplastic Syndromes - genetics; Myelodysplastic Syndromes - metabolism; Myelodysplastic Syndromes - pathology; Neoplasia; Neoplasm Transplantation; Oncogenes; Protein Isoforms - genetics; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Neoplasm - genetics; RNA, Neoplasm - metabolism; Signal Transduction; Transcription Factors - genetics; Transcription Factors - metabolism; Wnt Proteins - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2006-02-001594

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 β-catenin and synergistically enhanced the Wnt/β-catenin signaling pathway. Our data suggest that the constitutive expression of SALL4 causes MDS/AML, most likely through the Wnt/β-catenin pathway. Our murine model provides a useful platform to study human MDS/AML transformation, as well as the Wnt/β-catenin pathway's role in the pathogenesis of leukemia stem cells.