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Ex Vivo Expansion of Phenotypic and Transcriptomic Chronic Myeloid Leukemia Stem Cells

ABSTRACT: Despite decades of research, standard therapies remain ineffective for most leukemias, pushing toward an essential unmet need for targeted drug screens. Moreover, preclinical drug testing is an important consideration for success of clinical trials without affecting non-transformed stem cells. Using the transgenic chronic myeloid leukemia (CML) mouse model, we determine that leukemic stem cells (LSCs) are transcriptionally heterogenous with a preexistent drug-insensitive signature. To test targeting of potentially important pathways, we establish ex vivo expanded LSCs that have long-term engraftment and give rise to multilineage hematopoiesis. Expanded LSCs share transcriptomic signatures with primary LSCs including enrichment in Wnt, JAK-STAT, MAPK, mTOR and transforming growth factor b signaling pathways. Drug testing on expanded LSCs show that transforming growth factor b and Wnt inhibitors had significant effects on the viability of LSCs, but not leukemia-exposed healthy HSCs. This platform allows testing of multiple drugs at the same time to identify vulnerabilities of LSCs.

ORGANISM(S): Mus musculus

PROVIDER: GSE189368 | GEO | 2023/04/02

REPOSITORIES: GEO

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Ex Vivo Expansion of Phenotypic and Transcriptomic Chronic Myeloid Leukemia Stem Cells

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Project description:DNA Methyltransferase 3A (DNMT3A) is frequently mutated in various hematopoietic malignancies; however, the underlying oncogenic mechanisms remain elusive. Here, we report that DNMT3A mutational âhotspotâ at Arg882 (DNMT3A-R882H) cooperates with constitutively activated RAS in transforming murine hematopoietic stem/progenitor cells (HSPCs) ex vivo and inducing acute leukemias in vivo. DNMT3A-R882H potentiates aberrant transactivation of âstemnessâ gene expression programs, notably transcription factors Meis1, Hox-A, Mn1 and Mycn. Mechanistically, R882-mutated DNMT3A directly binds to cis-regulatory elements of these genes and induces focal CpG hypomethylation reminiscent of what was seen in human leukemias bearing DNMT3A R882 mutation. Furthermore, DNMT3A-R882H induced DNA hypomethylation facilitates gene enhancer/promoter activation and recruitment of Dot1l-associated transcription elongation machineries. Inactivation of Dot1l represses DNMT3AR882H-mediated stem cell gene dysregulation and acute leukemogenicity. In this dataset, we provided gene expression profiling data for (1) RH-RAS leukemia stem cells (RH-RAS LSCs), (2) LSCs transformed by MLL-AF9, (3) LSCs transformed by NUP98-JARID1A, and (4) Dot1l inhibitor-treated RH-RAS LSCs. Gene expression data were generated using Mouse Genome 430 2.0 Microarray (Affymetrix) for four independently derived RH-RAS LSC lines (termed as LSC RH-RAS #1, #2, #3 and #4), two RH-RAS LSC lines (LSC RH-RAS #1 and # 3) treated with 1 ÂµM SGC0946 (a Dot1l-specific small-molecule inhibitor) for 4 days, one MLL-AF9-transformed progenitor line and three NUP98-JARID1A transformed progenitor lines.

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