Back to Search
Start Over
Kdm6b regulates context-dependent hematopoietic stem cell self-renewal and leukemogenesis
- Source :
- Leukemia
- Publication Year :
- 2019
- Publisher :
- Springer Science and Business Media LLC, 2019.
-
Abstract
- The histone demethylase KDM6B (JMJD3) is upregulated in blood disorders, suggesting that it may have important pathogenic functions. Here we examined the function of Kdm6b in hematopoietic stem cells (HSC) to evaluate its potential as a therapeutic target. Loss of Kdm6b lead to depletion of phenotypic and functional HSCs in adult mice, and Kdm6b is necessary for HSC self-renewal in response to inflammatory and proliferative stress. Loss of Kdm6b leads to a pro-differentiation poised state in HSCs due to the increased expression of the AP-1 transcription factor complex (Fos and Jun) and immediate early response (IER) genes. These gene expression changes occurred independently of chromatin modifications. Targeting AP-1 restored function of Kdm6b-deficient HSCs, suggesting that Kdm6b regulates this complex during HSC stress response. We also show Kdm6b supports developmental context-dependent leukemogenesis for T-cell acute lymphoblastic leukemia (T-ALL) and M5 acute myeloid leukemia (AML). Kdm6b is required for effective fetal-derived T-ALL and adult-derived AML, but not vice versa. These studies identify a crucial role for Kdm6b in regulating HSC self-renewal in different contexts, and highlight the potential of KDM6B as a therapeutic target in different hematopoietic malignancies.
- Subjects :
- 0301 basic medicine
Jumonji Domain-Containing Histone Demethylases
cancer stem cell
Cancer Research
Myeloid
Carcinogenesis
T-Lymphocytes
Transcription factor complex
Biology
self-renewal
Hematopoietic stem cell
Article
Mice
03 medical and health sciences
0302 clinical medicine
medicine
Animals
Cell Self Renewal
epigenetics
Myeloid leukemia
Cell Differentiation
Hematology
Hematopoietic Stem Cells
AP-1
medicine.disease
Up-Regulation
3. Good health
Cell biology
Chromatin
Mice, Inbred C57BL
Leukemia, Myeloid, Acute
Leukemia
Haematopoiesis
030104 developmental biology
medicine.anatomical_structure
Oncology
030220 oncology & carcinogenesis
Stem cell
Transcription Factors
Subjects
Details
- ISSN :
- 14765551 and 08876924
- Volume :
- 33
- Database :
- OpenAIRE
- Journal :
- Leukemia
- Accession number :
- edsair.doi.dedup.....95733ca985239f045aaa71df0e1eb3f9