The Sox4/Tcf7l1 axis promotes progression of BCR-ABL-positive acute lymphoblastic leukemia.

Abstract

The transcription factor Sox4 plays an indispensable role in the development of early progenitor B cells from hematopoietic stem cells. However, its role in B-cell acute lymphoblastic leukemia, a malignant counterpart of normal progenitor B cells, is not fully understood. Here we show that SOX4 is highly expressed in human acute lymphoblastic leukemia cells. To systematically study the function of Sox4 in acute lymphoblastic leukemia, we established a genetically defined mouse leukemia model by transforming progenitor B cells carrying a floxed Sox4 allele and inducing deletion of the allele by the self-excising Cre recombinase. This model allowed us to work with two groups of leukemic cells that had either one copy or both copies of Sox4 deleted. We found that depletion of Sox4 in transformed cells in vitro reduced cell growth in vitro and the progression of leukemia in vivo. Moreover, depletion of Sox4 in leukemic cells in vivo prolonged the survival of the mice, suggesting that it could be a potential target in acute lymphoblastic leukemia therapy. Our microarray and bioChIP studies revealed that Tcf7l1 was the key gene directly regulated by Sox4. Knockdown of Tcf7l1 reduced cell proliferation, just as did knockout of Sox4, and ectopic expression of Tcf7l1 could reverse the effect of Sox4 knockout on cell proliferation. These data suggest that Sox4 and Tcf7l1 form a functional axis that promotes the progression of BCR-ABL-positive acute lymphoblastic leukemia.

• Authors: Haiqing Ma, Saradhi Mallampati, Yue Lu, Baohua Sun, Enze Wang, Xiaohong Leng, Yun Gong, Haifa Shen, C Cameron Yin, Dan Jones, Hesham M Amin, M James You, Patrick Zweidler-McKay, Yupo Ma, Hagop M Kantarjian, Ralph B Arlinghaus, Armand Glassman, Xiaoping Sun
• Journal: Haematologica (Haematologica) Vol. 99 Issue 10 Pg. 1591-8 (Oct 2014) ISSN: 1592-8721 [Electronic] Italy
• PMID: 24997151 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright© Ferrata Storti Foundation.

Chemical References

• RNA, Messenger
• SOXC Transcription Factors
• Transcription Factor 7-Like 1 Protein
• Fusion Proteins, bcr-abl

Topics

• Animals
• Cell Line, Tumor
• Cell Transformation, Neoplastic (genetics, metabolism)
• Cluster Analysis
• Disease Progression
• Fusion Proteins, bcr-abl (genetics)
• Gene Expression Profiling
• Gene Expression Regulation, Leukemic
• Humans
• Mice
• Mice, Transgenic
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (genetics, metabolism, mortality, pathology)
• RNA Interference
• RNA, Messenger (genetics, metabolism)
• SOXC Transcription Factors (genetics, metabolism)
• Transcription Factor 7-Like 1 Protein (genetics, metabolism)
• Tumor Burden (genetics)