Abstract
BCR-ABL1(+) precursor B-cell acute lymphoblastic leukemia (BCR-ABL1(+) B-ALL) is an aggressive hematopoietic neoplasm characterized by a block in differentiation due in part to the somatic loss of transcription factors required for B-cell development. We hypothesized that overcoming this differentiation block by forcing cells to reprogram to the myeloid lineage would reduce the leukemogenicity of these cells. We found that primary human BCR-ABL1(+) B-ALL cells could be induced to reprogram into macrophage-like cells by exposure to myeloid differentiation-promoting cytokines in vitro or by transient expression of the myeloid transcription factor C/EBPα or PU.1. The resultant cells were clonally related to the primary leukemic blasts but resembled normal macrophages in appearance, immunophenotype, gene expression, and function. Most importantly, these macrophage-like cells were unable to establish disease in xenograft hosts, indicating that lineage reprogramming eliminates the leukemogenicity of BCR-ABL1(+) B-ALL cells, and suggesting a previously unidentified therapeutic strategy for this disease. Finally, we determined that myeloid reprogramming may occur to some degree in human patients by identifying primary CD14(+) monocytes/macrophages in BCR-ABL1(+) B-ALL patient samples that possess the BCR-ABL1(+) translocation and clonally recombined VDJ regions.
Highlights
BCR–ABL1+ precursor B-cell acute lymphoblastic leukemia (BCR– ABL1+ B-ALL) is an aggressive hematopoietic neoplasm characterized by a block in differentiation due in part to the somatic loss of transcription factors required for B-cell development
BCR–ABL1+ B-ALL Blasts Reprogram into CD14hi/CD19lo Macrophage-Like Cells When Cultured in the Presence of Myeloid DifferentiationPromoting Cytokines
To investigate whether primary human BCR–ABL1+ B-ALL blasts could be induced to reprogram to the myeloid linage upon exposure to myeloid differentiationpromoting cytokines, we first sought to isolate a pure population of leukemic blasts, thereby excluding rare contaminating nonmalignant hematopoietic stem and myeloid progenitor cells
Summary
BCR–ABL1+ precursor B-cell acute lymphoblastic leukemia (BCR– ABL1+ B-ALL) is an aggressive hematopoietic neoplasm characterized by a block in differentiation due in part to the somatic loss of transcription factors required for B-cell development. The resultant cells were clonally related to the primary leukemic blasts but resembled normal macrophages in appearance, immunophenotype, gene expression, and function Most importantly, these macrophage-like cells were unable to establish disease in xenograft hosts, indicating that lineage reprogramming eliminates the leukemogenicity of BCR–ABL1+ B-ALL cells, and suggesting a previously unidentified therapeutic strategy for this disease. Rapino et al have shown that a subset of human B-ALL cell lines can be induced to reprogram to the myeloid lineage by forced expression of C/EBPα [10] These findings raise the possibility that primary human BCR–ABL1+ B-ALL blasts can be reprogrammed in a similar manner. Normal B-cell development requires successful passage through multiple developmental checkpoints (e.g., the expression of a functional pre–B-cell receptor) involving coordinated expression of multiple gene programs [13] Given these requirements, forcing malignant B-ALL cells to differentiate into mature, naïve B cells may not be possible. The high frequency of loss of these genes in BCR–ABL1+ B-ALL suggests that B-cell maturation arrest is critical to the pathogenesis of this disease
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
