TRANSCRIPTIONAL CONTROL OF LEUKEMOGENESIS BY THE CHROMATIN READER SGF29.
Karina BarbosaAnagha DeshpandeMarlenne Edith PeralesPing XiangRabi MuradAkula Bala PramodAnna MinkinaNeil Alistair RobertsonFiorella SchischlikXue LeiYounguk SunAdam BrownDiana AmendIrmela JeremiasJohn G DoenchKeith Keith HumphriesEytan RuppinJay A ShendurePrashant MaliPeter D AdamsAniruddha J DeshpandePublished in: Blood (2023)
Aberrant expression of stem-cell-associated genes is a common feature in acute myeloid leukemia (AML) and is linked to leukemic self-renewal and therapy resistance. Using AF10-rearranged leukemia as a prototypical example of the recurrently activated "stemness" network in AML, we screened for chromatin regulators that sustain its expression. We deployed a CRISPR-Cas9 screen with a bespoke domain-focused library and identified several novel chromatin-modifying complexes as regulators of the TALE domain transcription factor MEIS1, a key leukemia stem cell (LSC)-associated gene. CRISPR droplet sequencing revealed that many of these MEIS1 regulators coordinately controlled the transcription of several AML oncogenes. In particular, we identified a novel role for the Tudor-domain containing chromatin reader protein SGF29 in the transcription of AML oncogenes. Furthermore, SGF29 deletion impaired leukemogenesis in models representative of multiple AML subtypes in multiple AML subtype models. Our studies reveal a novel role for SGF29 as a non-oncogenic dependency in AML and identify the SGF29 Tudor domain as an attractive target for drug discovery.
Keyphrases
- transcription factor
- acute myeloid leukemia
- stem cells
- genome wide
- genome wide identification
- allogeneic hematopoietic stem cell transplantation
- crispr cas
- dna binding
- gene expression
- single cell
- drug discovery
- genome editing
- oxidative stress
- atrial fibrillation
- high throughput
- epithelial mesenchymal transition
- machine learning
- binding protein
- bone marrow
- cell therapy
- heat shock protein
- signaling pathway
- cancer stem cells
- replacement therapy