CD79a impacts central nervous system (CNS) infiltration of pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL)

Introducton:

CNS involvement at diagnosis and relapse remains one of the major problems in the treatment of ALL. Novel targets for the prediction of CNS involvement and its treatment are urgently required. Previous data from our group showed that components of the pre-B-cell receptor (pre-BCR) signalling machinery may promote CNS-infiltration. We therefore studied the role of the pre-BCR in CNS-infiltration of BCP-ALL cells.

Method:

Comparative RNA sequencing analyses were performed with patient derived xenograft (PDX) blasts isolated from the murine bone marrow and the CNS. Moreover, functional in vivo analyses were conducted using shRNA-mediated knockdown of CD79a in human BCP-ALL cell lines. Furthermore, a xenograft model with transformed B-cells from CD79a knockout mice was employed.

Results:

CD79a was upregulated in E2A-PBX1 positive PDX cells isolated from the mouse CNS. Knockdown of CD79a in the E2A-PBX1 positive cell line 697 did not impact overall leukemic burden and survival in xenograft mice, but resulted in a marked reduction of CNS infiltration. In a xenograft model using BCR-ABL transformed B-cells from CD79a knockout animals, the absence of CD79a delayed leukemic onset and resulted in a remarkably diminished degree of CNS-involvement.

Conclusion:

CD79a plays a pivotal role in CNS-infiltration in xenotransplantation models with human and murine BCP-ALL cells. CD79a may represent a novel therapeutic target and surrogate diagnostic parameter for CNS-involvement in this disease.