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Barbosa, K.O.* ; Deshpande, A.* ; Perales, M.E.* ; Xiang, P.* ; Murad, R.* ; Pramod, A.B.* ; Minkina, A.* ; Robertson, N.A.* ; Schischlik, F.* ; Lei, X.* ; Sun, Y.* ; Brown, A.* ; Amend, D. ; Jeremias, I. ; Doench, J.G.* ; Humphries, K.K.* ; Ruppin, E.* ; Shendure, J.A.* ; Mali, P.* ; Adams, P.D.* ; Deshpande, A.J.*

Transcriptional control of leukemogenesis by the chromatin reader SGF29.

Blood 143, 697-712 (2023)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Bone-marrow-cells; Hox Genes; H3k79 Methylation; Leukemia; Expression; Hematopoiesis; Proteomics; Acetylation; Maintenance; Inhibition
ISSN (print) / ISBN 0006-4971
e-ISSN 1528-0020
Journal Blood
Quellenangaben Volume: 143, Issue: 8, Pages: 697-712 Article Number: , Supplement: ,
Publisher American Society of Hematology
Publishing Place 2021 L St Nw, Suite 900, Washington, Dc 20036 Usa
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)
Grants Department of Defense Horizon Award
V Foundation for Cancer Research
Emerging Scientist Award from the Children's Cancer Research Fund
Luke Tatsu Johnson Foundation
Rally Foundation for Childhood Cancer Research
National Cancer Institute
National Institutes of Health