Involvement of Blnk and Foxo1 in tumor suppression in BCR-ABL1-transformed pro-B cells

Oncogenic Bcr-Abl kinase mimics pre-B cell receptor (pre-BCR) survival signals in BCR-ABL1-positive B-cell acute lymphoblastic leukemia (BCR-ABL1(+) B-ALL), driving B-cell progenitor malignant transformation; thus, defining a particularly unfavorable prognosis for patients. During B-cell development, pre-BCR differentiation signaling components terminate proliferative expansion and promote B-cell maturation. To study whether pre-BCR differentiation signaling components regulate the initiation and development of BCR-ABL1(+) B-ALL, the tumor suppression mechanism of differentiation-related signaling molecules in BCR-ABL1-transformed pro-B cells were analyzed. The results demonstrated that Bcr-Abl kinase activated the PI3K/Akt pathway, promoting cell growth, and upregulated Aid expression, increasing genomic instability in pro-B cells. These findings suggest that Bcr-Abl kinase mediates pro-B cell malignant transformation. Furthermore, the present data revealed that BCR-ABL1 oncogenic stress triggered enhanced expression of B-cell differentiation components B-cell linker (Blnk) and forkhead box protein O1 (Foxo1) in BCR-ABL1 transformed pro-B cells. Using the CRISPR/Cas9-mediated Blnk or Foxo1 knockout BCR-ABL1-transformed pro-B cells, it was identified that, in BCR-ABL1-transformed pro-B cells, Blnk and Foxo1 reduced Bcr-Abl kinase activity to induce cell cycle arrest and decrease genomic instability. In addition, Blnk suppressed the PI3K/Akt pathway to reduce Foxo1 phosphorylation and heighten the Foxo1 activity, indicating that, in BCR-ABL1-transformed pro-B cells, Foxo1 participated in the regulation of Bcr-Abl kinase by Blnk. The present data highlighted the antitumor mechanisms of Blnk and Foxo1 in the regulation of Bcr-Abl kinase, and thus, may offer an alternative therapeutic strategy to Bcr-Abl kinase regulation in BCR-ABL1(+) B-ALL.