Myeloid reprogramming B cell acute lymphoblastic leukemia
Abstract/Contents
- Abstract
- Five-year survival rates for adult B-cell acute lymphoblastic leukemia (B-ALL) remain dismal, and novel approaches will be required to improve outcomes. I enumerate several important advances in a promising treatment strategy that entails reprogramming malignant B-cell precursors to macrophage-like 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 factors 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. Critically, reprogramming patient leukemic blasts to myeloid cells ablates their tumorigenicity in immunocompromised mice. We further 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. Additionally, we found that small molecule drugs augment C/EBPα-driven myeloid reprogramming. We employed a whole genome CRISPR-Cas9 screen and identified genetic knockouts that improve reprogramming in a human cell line model of B-ALL. We validated two targets, EHMT2 and EHMT1, resulting from this screen for their ability to increase myeloid reprogramming. These genes encode protein products G9a and GLP, respectively, which form a heteroduplex capable of conferring the transcriptionally repressive histone mark H3K9me2. Ablating G9a expression, and subsequently H3K9me2 deposition in chromatin, speeds the transition of cells from a lymphoid to a myeloid state. The addition of A366, a small molecule inhibitor of G9a, induced higher frequency and more rapid myeloid reprogramming. Last, we found that the addition of A366 improved chromatin access measured by ATAC-seq at a number of important myeloid loci. The use of a small molecule in myeloid reprogramming is an important proof of principle for the clinical feasibility of reprogramming technology for hematologic malignancy. We built upon the principles of cell reprogramming, developing a new cytokine-dependent method of myeloid reprogramming, and discovering a novel small molecule target that improves myeloid reprogramming
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2020; ©2020 |
| Publication date | 2020; 2020 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Dove, Christopher George |
|---|---|
| Degree supervisor | Majeti, Ravindra, 1972- |
| Thesis advisor | Majeti, Ravindra, 1972- |
| Thesis advisor | Alizadeh, Ash |
| Thesis advisor | Levy, Ronald, 1941 December 6- |
| Thesis advisor | Winslow, Monte |
| Degree committee member | Alizadeh, Ash |
| Degree committee member | Levy, Ronald, 1941 December 6- |
| Degree committee member | Winslow, Monte |
| Associated with | Stanford University, Cancer Biology Program. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Christopher George Dove |
|---|---|
| Note | Submitted to the Cancer Biology Program |
| Thesis | Thesis Ph.D. Stanford University 2020 |
| Location | electronic resource |
Access conditions
- Copyright
- © 2020 by Christopher George Dove
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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