Characterizing cell-autonomous and non-autonomous contributions of RUNX1 loss in hematopoiesis and leukemogenesis using genetically engineered primary human cells
Abstract/Contents
- Abstract
- Disease-initiating mutations in the transcription factor RUNX1 occur as germline and somatic events that cause leukemias with particularly poor prognosis. However, the role of RUNX1 in leukemogenesis is not fully understood and effective therapies for RUNX1-mutant leukemias remain elusive. Here, we use primary patient samples and a RUNX1 knockout model in primary human hematopoietic cells to investigate how RUNX1 loss alters human hematopoietic develop and contributes to leukemic progression and to identify targetable vulnerabilities. RUNX1 loss expanded monocytic differentiation at the expense of erythro-megakaryocytic cells due to dysregulation of key transcription factors regulating erythro-megakaryocytic (GATA1, SRF) and myeloid (NFB) differentiation. Surprisingly, RUNX1 loss decreased proliferative capacity and stem cell function. However, RUNX1-deficient cells selectively upregulated the interleukin-3 (IL-3) receptor. Exposure to IL-3, but not other JAK/STAT cytokines, rescued RUNX1 KO proliferative and competitive defects. Further, we demonstrated that RUNX1 loss repressed JAK/STAT signaling and rendered RUNX1-deficient cells sensitive to JAK inhibitors. Our study identifies a dependency of RUNX1-mutant leukemias on IL-3/JAK/STAT signaling, which may enable these aggressive blood cancers to be targeted with existing agents
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 | 2023; ©2023 |
| Publication date | 2023; 2023 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Fan, Amy Chaohua |
|---|---|
| Degree supervisor | Majeti, Ravindra, 1972- |
| Thesis advisor | Majeti, Ravindra, 1972- |
| Thesis advisor | Chan, Charles K. F. (Charles Kwok Fai), 1975-2024 |
| Thesis advisor | Nakauchi, Hiromitsu, 1952- |
| Thesis advisor | Wu, Joy |
| Degree committee member | Chan, Charles K. F. (Charles Kwok Fai), 1975-2024 |
| Degree committee member | Nakauchi, Hiromitsu, 1952- |
| Degree committee member | Wu, Joy |
| Associated with | Stanford University, School of Medicine |
| Associated with | Stanford University, Program in Immunology |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Amy Chaohua Fan |
|---|---|
| Note | Submitted to the Program in Immunology |
| Thesis | Thesis Ph.D. Stanford University 2023 |
| Location | https://purl.stanford.edu/tc622jj4926 |
Access conditions
- Copyright
- © 2023 by Amy Chaohua Fan
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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