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

ABSTRACT: 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.

SUBMITTER: Zhang P 

PROVIDER: S-EPMC7757083 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature