Reprogramming of primary human Philadelphia chromosome-positive B cell acute lymphoblastic leukemia cells into nonleukemic macrophages

• Published in: Proceedings of the National Academy of Sciences - PNAS 2015-03, Vol.112 (13), p.4074-4079
• Main Authors: McClellan, James Scott, Dove, Christopher, Gentles, Andrew J., Ryan, Christine E., Majeti, Ravindra
• Format: Article
• Language: English
• Subjects: Adult; Aged; Animals; Antigens, CD19 - metabolism; B-Lymphocytes - metabolism; bacteria; Biological Sciences; Cell Culture Techniques; Cell Differentiation; Cells; Chromosomes; Cytokines; Cytokines - metabolism; Female; Fusion Proteins, bcr-abl - genetics; Fusion Proteins, bcr-abl - metabolism; Gene expression; Humans; Leukemia; leukocytes; Leukocytes - cytology; Lipopolysaccharide Receptors - metabolism; lymphocytic leukemia; macrophages; Macrophages - cytology; Male; Mice; Mice, Transgenic; Middle Aged; neoplasm cells; Patients; Philadelphia Chromosome; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Prognosis
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1413383112

Significance Precursor B cell acute lymphoblastic leukemia (B-ALL) is an aggressive cancer of white blood cells with a poor prognosis. The cancerous cells in this disease are immature B cells, which are unable to fully differentiate into normal B cells. We show here that cancerous cells from B-ALL patients can be reprogrammed, causing them to change into cells that resemble normal macrophages and can perform macrophage-associated functions such as the consumption of bacteria. Importantly, unlike typical B-ALL cells, these reprogrammed cells are no longer able to cause disease in immunodeficient mice. Finally, we show that this reprogramming process may occur to some degree in patients with B-ALL. This indicates that reprogramming B-ALL cells into macrophages might represent a previously unidentified therapeutic strategy. 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.