Sox4 is required for the survival of pro-B cells.
The development of mature B cells from hematopoietic stem cells is a strictly orchestrated process involving multiple regulatory genes. The transcription factor Sox4 is required for this process, but its role has not been systematically studied, and the underlying mechanisms remain unknown. To determine when and how Sox4 functions in the stepwise process of B cell development, we used mice harboring conditional null alleles for Sox4 and a Cre transgene. Sox4 deletion in hematopoietic stem cells almost entirely eliminated pro-B cells in both fetal livers and adult bone marrow, resulting in a severe deficiency in later stage B cells, including circulating mature B cells. Sox4-deficient pro-B cells, particularly those expressing the stem cell factor receptor c-Kit, readily underwent apoptosis, and even more so when c-Kit activity was inhibited by imatinib. C-Kit-expressing pro-B cells showed decreased activation of the c-Kit downstream protein Src upon Sox4 deletion. Likewise, the level of the anti-apoptotic Bcl2 protein was decreased in residual pro-B cells, and its restoration using a Bcl2 transgene allowed not only partial rescue of pro-B cell survival but also B cell maturation in the absence of Sox4. Our findings indicate that Sox4 is required for the survival of pro-B cells and may functionally interact with c-Kit and Bcl2.
Department of Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Baohua
B
Sun
Saradhi
S
Mallampati
Yun
Y
Gong
Donghai
D
Wang
Véronique
V
Lefebvre
Xiaoping
X
Sun
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D001549:Benzamides; D001853:Bone Marrow / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005333:Fetus; D005786:Gene Expression Regulation / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D000068877:Imatinib Mesylate; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D018655:Lymphocyte Count; D051379:Mice; D018345:Mice, Knockout; D010879:Piperazines / Q000494:pharmacology; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D055751:SOXC Transcription Factors / Q000172:deficiency / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D019076:Transgenes; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000378:metabolism
D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D055751:SOXC Transcription Factors; C489990:Sox4 protein, mouse; D051025:bcl-Associated Death Protein; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D016392:Proto-Oncogene Proteins pp60(c-src); C045073:Cre recombinase; D019426:Integrases