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

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.

Clonal conversion of B lymphoid leukemia reveals cross-lineage transfer of malignant states

“…This finding is in line with existing literature (Rapino et al 2013;McClellan et al 2015); however, because C/ EBP proteins may act as tumor suppressors (Pabst et al 2001;Nerlov 2004), continued ectopic expression of C/ EBP proteins from the retroviral insertions might counteract the formation of myeloid leukemia. In order to explore this possibility, we took advantage of a C/EBPα retrovirus carrying the protein fused to a tamoxifen (4-OHT)-responsive estrogen receptor (ER) protein, allowing us to modulate the nuclear localization of the protein via the addition of 4-OHT.…”

“…Significant up-regulation and down-regulation are shown with red and blue asterisks, respectively; ( * ) P < 0.05; ( * * * * ) P < 0.0001. apparent delay in the expansion of leukemia cells (Figs. 4G, 5E) more in line with data suggesting that conversion of the B-lineage cells to myeloid lineages reduces the malignancy of the cells (Rapino et al 2013;McClellan et al 2015) in these experimental settings. In leukemia patients, it is more common to find ALAL with shared B and myeloid characteristics (Jennings and Foon 1997;Craig and Foon 2008;Manola 2013), and the dose of PAX5 has also been suggested to be involved in the formation of biphenotypic leukemia, which is characterized by a combined expression of B-lineage and myeloid lineage markers (Simmons et al 2012).…”

“…It has been reported that the expression of C/EBP proteins causes a phenotypic conversion of B-lineage tumor cells to generate myeloid cells (Xie et al 2004;Bussmann et al 2009) with reduced malignant potential (Rapino et al 2013;McClellan et al 2015). To explore the ability of …”

Concise Review: Recent Advances in the In Vitro Derivation of Blood Cell Populations

“…The overexpression of FLI1 and ERG was shown to reprogram human bone marrow-derived erythroblasts to megakaryocytes with the ability to produce functional platelets [66]. Ectopic expression of PU.1 in leukemic B cells not only reprogramed these malignant cells to macrophages but also impaired tumorigenicity [67]. Together, these studies indicate that transdifferentiation approaches can be used to generate many functional mature blood cell types.…”

Immunophenotypic Profile in Adult Patients with Acute Leukemia Association with Clinical Feature: Fluorescence Cytometry Quantitative Analysis

“…TdT expression, lack of surface light chains, and variable genetic alterations are also common [24] B lymphoblastic leukemia (B-ALL) is a neoplasm of hematopoietic precursor cells committed to the B-cell lineage [25]. Immunophenotypic analysis is an essential component of the diagnostic work-up of acute leukemias (AL), and flow cytometry (FC) is the preferred method of analysis (Xin, 2014).…”