AML senescence capacity is a unifying outcome predictor and plastic APL classifier
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ABSTRACT:
PROVIDER: PRJNA1222893 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32324230.fastq.gz | Fastqsanger.gz | |||
| SRR32324231.fastq.gz | Fastqsanger.gz | |||
| SRR32324232.fastq.gz | Fastqsanger.gz | |||
| SRR32324233.fastq.gz | Fastqsanger.gz | |||
| SRR32324234.fastq.gz | Fastqsanger.gz |
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Project description:BACKGROUND Acute myeloid leukemia (AML) is a highly heterogeneous disease. The predictive role of therapy-induced senescence (TIS) in cancer treatment in general and newly diagnosed (nd) AML patients in particular is undetermined. METHODS We established a flow cytometry-based senescence assay to detectsenescence in primary patient blasts to ex vivo chemotherapy (daunorubicin or cytarabine) in patients with newly diagnosed (nd) non-M3 AML. Bulk and single-cell analyses assessed gene expression and recurrent AML mutations. TIS-related gene signatures were interrogated in additional AML patient cohorts. Computational analyses, chromatin immunoprecipitation sequencing and other functional assays characterized TIS-related leukemia biology. RESULTS Ex vivo-determined TIS capacity predicted superior disease-free and overall survival in three independent cohorts comprising 92 patients with nd non-M3 AML across diverse (cyto-)genetic subgroups. Subsequent treatment with Bcl2 inhibitors venetoclax or navitoclax demonstrated their senescence-preferential killing. By interrogating 977 nd all-subtype AML patients from three additional independent cohorts, a TIS-derived gene classifier unexpectedly identified M3-AML/acute promyelocytic leukemia cases with very high accuracy in a PML-RARA-agnostic fashion. We found the polycomb-repressive complex 2 component Suz12 to regulate this classifier. Non-M3-AML cell lines in TIS differentiated upon all-trans retinoic acid (ATRA), or died in response to the Suz12-targeting histone deacetylase (HDAC) inhibitor panobinostat. CONCLUSIONS TIS predicts superior long-term outcome in nd AML and confers unifying plasticity across molecularly highly diverse AML subtypes towards an M3-like state, which enables consolidative senolysis by Bcl2 family or HDAC inhibition, or senodifferentiation by ATRA as novel plasticity-based treatment concepts.
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Project description:We profiled transcripts from sorted phloem cells of wild-type and apl mutants to identify the genes regulated by APL in phloem. We profiled transcripts from sorted phloem cells of wild-type and apl mutants to identify the genes regulated by APL in phloem.
2014-08-25 | GSE55222 | GEO
Project description:We profiled transcripts from sorted phloem cells of wild-type and apl mutants to identify the genes regulated by APL in phloem. We profiled transcripts from sorted phloem cells of wild-type and apl mutants to identify the genes regulated by APL in phloem. Three biological replicates for control WT and apl mutants were used in thes study. Root tissue was protoplasted and sorted using fluorescence-activated cell sorting (FACS). Total RNA was extracted from GFP+ protoplasts.
2014-08-25 | E-GEOD-55222 | biostudies-arrayexpress
Project description:Acute Promyelocytic Leukemia (APL) is characterized by the t(15;17)(q22;q11.2) translocation, which creates a PML-RARA fusion gene that can initiate APL in mice. To discover cooperating mutations in this model, we sequenced a mouse APL genome to 15.6x haploid coverage, and discovered three somatic, non-synonymous mutations, of which one (Jak1 V657F) was recurrent. This mutation is identical to the JAK1 V658F mutation previously found in human APL and ALL samples. JAK1 V658F cooperates in vivo with PML-RARA, causing a rapidly fatal leukemia. We also discovered a somatic 150kb deletion involving the Kdm6a/Utx gene in the mouse APL genome; 3/14 additional mouse APL samples had similar deletions involving Kdm6a/Utx. Kdm6A/Utx, a histone H3K27 demethylase, was also deleted in 1/150 human AML samples tested. Whole genome sequencing of mouse cancer genomes provides an unbiased approach for discovering functionally relevant mutations that are also present in human leukemias.
2010-12-30 | GSE26130 | GEO
Project description:Acute Promyelocytic Leukemia (APL) is characterized by the t(15;17)(q22;q11.2) translocation, which creates a PML-RARA fusion gene that can initiate APL in mice. To discover cooperating mutations in this model, we sequenced a mouse APL genome to 15.6x haploid coverage, and discovered three somatic, non-synonymous mutations, of which one (Jak1 V657F) was recurrent. This mutation is identical to the JAK1 V658F mutation previously found in human APL and ALL samples. JAK1 V658F cooperates in vivo with PML-RARA, causing a rapidly fatal leukemia. We also discovered a somatic 150kb deletion involving the Kdm6a/Utx gene in the mouse APL genome; 3/14 additional mouse APL samples had similar deletions involving Kdm6a/Utx. Kdm6A/Utx, a histone H3K27 demethylase, was also deleted in 1/150 human AML samples tested. Whole genome sequencing of mouse cancer genomes provides an unbiased approach for discovering functionally relevant mutations that are also present in human leukemias. DNA from 15 mouse APL tumors on the Bl/6 Taconic background (F10), DNA from one WT 129/SvJ mouse spleen, and pooled DNA derived from the spleens of 6-week-old, wild type, Bl/6 Taconic (parental strain) mice were analyzed using the Nimblegen Mouse CGH 3x720K WGT platform.
2010-12-30 | E-GEOD-26130 | biostudies-arrayexpress
Project description:Acute Promyelocytic Leukemia (APL) is characterized by the t(15;17)(q22;q11.2) translocation, which creates a PML-RARA fusion gene that can initiate APL in mice. To discover cooperating mutations in this model, we sequenced a mouse APL genome to 15.6x haploid coverage, and discovered three somatic, non-synonymous mutations, of which one (Jak1 V657F) was recurrent. This mutation is identical to the JAK1 V658F mutation previously found in human APL and ALL samples. JAK1 V658F cooperates in vivo with PML-RARA, causing a rapidly fatal leukemia. We also discovered a somatic 150kb deletion involving the Kdm6a/Utx gene in the mouse APL genome; 3/14 additional mouse APL samples had similar deletions involving Kdm6a/Utx. Kdm6A/Utx, a histone H3K27 demethylase, was also deleted in 1/150 human AML samples tested. Whole genome sequencing of mouse cancer genomes provides an unbiased approach for discovering functionally relevant mutations that are also present in human leukemias.
2010-12-29 | GSE26128 | GEO
Project description:Acute Promyelocytic Leukemia (APL) is characterized by the t(15;17)(q22;q11.2) translocation, which creates a PML-RARA fusion gene that can initiate APL in mice. To discover cooperating mutations in this model, we sequenced a mouse APL genome to 15.6x haploid coverage, and discovered three somatic, non-synonymous mutations, of which one (Jak1 V657F) was recurrent. This mutation is identical to the JAK1 V658F mutation previously found in human APL and ALL samples. JAK1 V658F cooperates in vivo with PML-RARA, causing a rapidly fatal leukemia. We also discovered a somatic 150kb deletion involving the Kdm6a/Utx gene in the mouse APL genome; 3/14 additional mouse APL samples had similar deletions involving Kdm6a/Utx. Kdm6A/Utx, a histone H3K27 demethylase, was also deleted in 1/150 human AML samples tested. Whole genome sequencing of mouse cancer genomes provides an unbiased approach for discovering functionally relevant mutations that are also present in human leukemias. Spleens from Bl/6 Taconic mice were harvested and total RNA was extracted. A total of 15 specimens were analyzed using the Affymetrix Mouse Exon 1.0 ST platform.
2010-12-29 | E-GEOD-26128 | biostudies-arrayexpress
Project description:CGH microarray in a patient with variant APL
2012-12-19 | GSE42984 | GEO
Project description:Nanopore sequencing for an APL patient
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Project description:RARA haploinsufficiency is an invariable consequence of t(15;17) reciprocal translocations in acute promyelocytic leukemia (APL). Furthermore, retinoids and RARA activity have been implicated in hematopoietic self-renewal, lineage commitment and neutrophil maturation. We and others therefore predicted that RARA haploinsufficiency would contribute to APL pathogenesis. To test this hypothesis we crossed RARA+/- mice with mice expressing PML-RARA from the Cathepsin G locus (mCG-PR). We found that RARA haploinsufficiency cooperated with PML-RARA, only modestly influencing the pre-leukemic and leukemic phenotype. Bone marrow from mCG-PR+/- x RARA+/- mice had decreased numbers of mature myeloid cells, increased ex vivo myeloid cell proliferation and an increased competitive advantage following transplantation. RARA haploinsufficiency did not alter mCG-PR dependent leukemic latency or penetrance, but did influence the distribution of leukemic cells; mCG-PR+/- x RARA+/- mice presented more commonly with low to normal white blood cell counts and with myeloid infiltration of lymph nodes. APL arising in these mice was responsive to ATRA, and had virtually no differences in expression profiling compared to tumors arising in mCG-PR+/- x RARA+/+ mice. These phenotypes were dependent on PML-RARA activity, since they were not detected in RARA+/- mice in the absence of the mCG-PR transgene. These data show that RARA haploinsufficiency (like PML haploinsufficiency and RARA-PML) can cooperate with PML-RARA to influence the pathogenesis and phenotype of APL in mice, but that PML-RARA is the driver of t(15;17) APL.
2010-07-29 | GSE23291 | GEO