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A niche driven mechanism determines response and a mutation-independent therapeutic approach for myeloid malignancies.

ABSTRACT: A niche driven mechanism determines response and a mutation-independent therapeutic approach for myeloid malignancies.

PROVIDER: PRJNA1094882 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28513935_1.fastq.gz	Fastqsanger.gz
	SRR28513935_2.fastq.gz	Fastqsanger.gz
	SRR28513936_1.fastq.gz	Fastqsanger.gz
	SRR28513936_2.fastq.gz	Fastqsanger.gz
	SRR28513937_1.fastq.gz	Fastqsanger.gz

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A niche driven mechanism determines response and a mutation-independent therapeutic approach for myeloid malignancies

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Project description:Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) remain resistant to standard of care (SOC) and targeted therapies. Here, we identify an oncogenic signal from the niche as a mechanism determining response to all-trans-retinoic acid (ATRA), a regiment with disparate results in AML. In reported clinical trials responsiveness to ATRA correlates with activation of b-catenin/JAG1 in osteoblasts and Notch1 signaling in MDS/AML cells. ATRA inhibits osteoblastic b-catenin activation in patients and leukemic mice and thus suppresses patient MDS/AML cell growth and survival and promotes their differentiation independent of cytogenetics and mutational profile. ATRA also improves disease outcome in mice with no evidence of relapse and a superior safety profile as compared to SOC. A circulating skeletal stem cell population expressing activated b-catenin allows patient stratification and monitoring treatment response. A human blocking antibody against JAG1 further improves efficacy, curing mice from leukemia and maintaining the beneficial effects on patient-derived MDS/AML cells. These findings provide a mechanistic biomarker for immediate ATRA repurposing in MDS/AML and demonstrate the therapeutic potential of targeting the niche to evade relapse and overcome toxicity.

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