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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: PRJNA1160801 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR30656675_1.fastq.gz	Fastqsanger.gz
	SRR30656675_2.fastq.gz	Fastqsanger.gz
	SRR30656676_1.fastq.gz	Fastqsanger.gz
	SRR30656676_2.fastq.gz	Fastqsanger.gz
	SRR30656677_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:Myeloid cancers such as 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 regimen with disparate results in AML. In samples from clinical trials, responsiveness to ATRA correlates with activation of b-catenin/JAG1 in osteoblastic lineage cells and Notch1 signaling in MDS/AML cells of patients. ATRA inhibits b-catenin activation in patients and leukemic mice. As a result, it specifically suppresses growth and survival and promotes differentiation of MDS/AML cells solely from patients with active b-catenin/JAG1 signaling. This event is independent of cytogenetics and mutational profile. ATRA also improves disease outcome in mice with no evidence of relapse and a superior safety profile 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 results demonstrate a niche-directed therapeutic approach, tailored to at least 1/3 of MDS/AML patients that can evade relapse and overcome SOC toxicity, highlighting the therapeutic potential of targeting the niche. b-catenin activation provides an explanation for the differential response to ATRA and a mechanistic biomarker for immediate ATRA repurposing in myeloid malignancies, potentially extending in a broad range of cancers.

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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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