Abstract
B-Cell CLL/Lymphoma 6 (BCL6) is a proto-oncogene that is highly expressed in acute lymphoblastic leukemia (ALL). BTB and CNC Homology 1 Basic Leucine Zipper Transcription Factor 2 (BACH2) is a suppressor of transcription. The BACH2–BCL6 balance controls selection at the pre-B cell receptor checkpoint by regulating p53 expression. However, the underlying mechanism and the clinical relevance of the BCL6/BACH2 axis are unknown. Here, we found that Ikaros, a tumor suppressor encoded by IKZF1, directly binds to both the BCL6 and BACH2 promoters where it suppresses BCL6 and promotes BACH2 expression in B-cell ALL (B-ALL) cells. Casein kinase 2 (CK2) inhibitors increase Ikaros function thereby inhibiting BCL6 and promoting BACH2 expression in an Ikaros-dependent manner. We also found that the expression of BCL6 is higher while BACH2 expression is lower in patients with B-ALL than normal bone marrow control. High BCL6 and low BACH2 expression is associated with high leukemic cell proliferation, unfavorable clinical and laboratory features, and inferior outcomes. Moreover, IKZF1 deletion is associated with high BCL6 and low BACH2 expression in B-ALL patients. CK2 inhibitors increase Ikaros binding to the promoter of BCL6 and BACH2 and suppress BCL6 while promoting BACH2 expression in the primary B-ALL cells. Our data indicates that Ikaros regulates expression of the BCL6/BACH2 axis in B-ALL. High BCL6 and low BACH2 expression are associated with Ikaros dysregulation and have a potential effect on the development of B-ALL.
Highlights
Acute lymphoblastic leukemia (ALL) is one of the most common hematologic malignancies
The BCL6high cohort had a higher frequency of IKZF1 deletion and BCR/ABL1 fusion compared to BCL6low cohort (45.8% vs. 13.9%, P=0.006; 67.6% vs. 39.0%, P=0.012) as determined using chi-squared tests
We found that B-Cell CLL/Lymphoma 6 (BCL6) is highly expressed but BACH2 is downregulated in patients
Summary
Acute lymphoblastic leukemia (ALL) is one of the most common hematologic malignancies. ALL remains a major cause of death in childhood and causes significant adult mortality. Understanding the mechanisms underlying its leukemogenesis and developing more effective therapeutic approaches could be very helpful for reducing the cancer death toll in both children and adults. More recent work has highlighted the impact of BCL6 on immature and malignant hematopoietic cells [18]. Increased expression of BCL6 in chronic myelogenous leukemia (CML) and ALL has been shown to protect leukemic cells from chemotherapy-induced DNA damage through the repression of p53-induced apoptosis [19,20]. In ALL cells, increased expression of BCL6 results in a tolerance to DNA damage which subsequently increases survival during BCR-ABL1 kinase inhibition [30]
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