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Gene regulation in t(6;9) AML resembles that of FLT3-ITD/NPM1 AML with an altered HOX/MEIS axis [RNA-seq]

ABSTRACT: Acute Myeloid Leukemia (AML) represents a heterogeneous group of hematological malignancies. The t(6;9)(p23;q34) translocation, giving rise to the DEK::NUP214 fusion protein, is a rare mutation which produces a highly aggressive AML associated with extremely poor prognosis. Here, we utilise genome-wide chromatin accessibility to elucidate how a normal gene regulatory networks is disrupted by DEK::NUP214. We find that DEK::NUP214 AML forms a specific GRN related to that of mutant NPM1 AML, but also displays an elevated leukemic stem cell signature, suggesting both similar and unique therapeutic vulnerabilities.

ORGANISM(S): Homo sapiens

PROVIDER: GSE240267 | GEO | 2024/01/04

REPOSITORIES: GEO

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Gene regulation in t(6;9) AML resembles that of FLT3-ITD/NPM1 AML with an altered HOX/MEIS axis [DNase-hypersensitivity]

Project description:Acute Myeloid Leukemia (AML) represents a heterogeneous group of hematological malignancies. The t(6;9)(p23;q34) translocation, giving rise to the DEK::NUP214 fusion protein, is a rare mutation which produces a highly aggressive AML associated with extremely poor prognosis. Here, we utilise genome-wide chromatin accessibility to elucidate how a normal gene regulatory networks is disrupted by DEK::NUP214. We find that DEK::NUP214 AML forms a specific GRN related to that of mutant NPM1 AML, but also displays an elevated leukemic stem cell signature, suggesting both similar and unique therapeutic vulnerabilities.

2024-01-04 | GSE240268 | GEO

DEK/NUP214 SILAC interactormics analysis

Project description:Among most of leukemogenic fusion proteins the aberrant localization that the translocation partners are forced in when compared to their wt counterparts contributes to leukemogenesis most likely by a sequester of interaction partners. The aim was to disclose the role of localization of DEK/NUP214 and the related sequester of proteins interacting with DEK/NUP214 for the induction t(6;9)- AML. The pathways indispensable for the induction of the leukemogenic phenotype were worked out by comparing the interactome of the full-length fusion protein to that of biologiaclly-dead mutants.

2022-10-14 | PXD031885 | Pride

Gene regulation in t(6;9) AML resembles that of FLT3-ITD/NPM1 AML with an altered HOX/MEIS axis

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-01-04 | GSE240272 | GEO

AML HLA Ligandome reveals mutated NPM1 as a recurrent neoantigen

Project description:Somatic mutations in cancer are a potential source of cancer specific neoantigens. Acute myeloid leukemia (AML) has common recurrent mutations shared between patients in addition to private mutations specific to individuals. We hypothesized that neoantigens derived from recurrent shared mutations would be attractive targets for future immunotherapy and sought to study the Class I and II HLA ligandomes of thirteen primary AML tumor samples and two AML cell lines (OCI-AML3 and MV4-11) using mass spectrometry. We identified two endogenous, mutation-bearing HLA Class I ligands from NPM1, which are predicted to bind the common HLA haplotypes, HLA-A*03:01 and HLA-A*02:01 respectively. We further derived CD8+ T cells from healthy donor peripheral blood samples which bound mutant-peptide loaded A*03:01 and A*02:01 tetramers, suggesting a new source of NPM1 mutation-specific T cell receptors (TCRs) for future evaluation. Since NPM1 is mutated in approximately one-third of patients with AML, the finding of endogenous NPM1 neoantigens supports future studies evaluating immunotherapeutic approaches against this target, for this subset of patients with AML.

2019-07-17 | PXD012083 | Pride

Implications of the miR-10 family in chemotherapy response of NPM1 mutated AML

Project description:Nucleophosmin mutated AML (NPM1mut-AML) patients have a high rate of complete remission (CR) to induction chemotherapy. However, the mechanisms responsible for such effects are unknown. Since miR-10 family members are expressed at high levels in NPM1mut-AML, we evaluated whether these microRNAs could predict chemotherapy response in AML. We found that high baseline miR-10 family expression in 54 untreated cytogenetically heterogeneous AML patients was associated with achieving CR. However, when we included NPM1 mutation status in the multivariable model, there was a significant interaction effect between miR-10a-5p expression and NPM1 mutation status. Similar results were observed when using a second cohort of 183 cytogenetically normal older (ageM-bM-^IM-%60 years) AML patients. Loss and gain of function experiments using miR-10a-5p in cell lines and primary blasts did not demonstrate any effect in apoptosis or cell proliferation at baseline or after chemotherapy. These data support a bystander role for the miR-10 family in NPM1mut-AML. Pretreatment miRNA expression was analyzed in 54 de novo adult AML patients obtained from the MD Anderson Cancer Center Leukemia Tissue Bank (LTB) using the Ohio State University (OSU) miRNA microarray (ver.3).

2014-05-01 | E-GEOD-55519 | biostudies-arrayexpress

AML with mutated NPM1 carrying a normal or aberrant karyotype show overlapping features

Project description:AML with mutated NPM1 usually carries normal karyotype (NK) but it may harbor chromosomal aberrations whose significance remains unclear. We addressed this question in 631 AML patients with mutated/cytoplasmic NPM1. An abnormal karyotype (AK) was present in 93/631 cases (14.7%), the most frequent abnormalities being +8, +4, -Y, del(9q), +21. Chromosome aberrations in NPM1-mutated AML were similar to, but occurred less frequently than additional chromosome changes found in other AML with recurrent cytogenetic abnormalities according to WHO classification. Four of the 31 NPM1-mutated AML patients karyotyped at different time points had NK at diagnosis but AK at relapse: del(9q) (n=2), t(2;11) (n=1), inv(12) (n=1). NPM1-mutated AML with NK or AK showed overlapping morphological, immunophenotypic (CD34-negativity) and gene expression profile (downregulation of CD34 and upregulation of HOX genes). No difference in survival was observed among NPM1-mutated AML patients independently of whether they carried a normal or abnormal karyotype, the NPM1-mutated/FLT3-ITD negative cases showing the better prognosis. Findings in our patients point to chromosomal aberrations as secondary events, reinforce the concept that NPM1 mutation is a founder genetic lesion and indicate that NPM1-mutated AML should be clinically handled as one entity, irrespective of the karyotype. All bone marrow samples were obtained from untreated patients at the time of diagnosis. Cells used for microarray analysis were collected from the purified fraction of mononuclear cells after Ficoll density centrifugation.

2009-06-01 | E-GEOD-16015 | biostudies-arrayexpress

Causal linkage of presence of mutant NPM1 to efficacy of novel therapeutic agents against AML cells with mutant NPM1 [ChIP-Seq]

Project description:In AML with NPM1 mutation causing cytoplasmic dislocation of NPM1, treatments with menin inhibitor (MI) and standard AML chemotherapy yield complete remissions. However, the causal and mechanistic linkage of mtNPM1 to the efficacy of these agents has not been definitively established. Utilizing CRISPR-Cas9 editing to knock-out (KO) or knock-in a copy of mtNPM1 in AML cells, present studies demonstrate that KO of mtNPM1 from AML cells abrogates sensitivity to MI, selinexor (exportin inhibitor) and cytarabine. Conversely, the knock-in of a copy of mtNPM1 markedly sensitized AML cells to treatment with MI or cytarabine. Following AML therapy, most elderly patients with AML with mtNPM1 and co-mutations in FLT3 suffer AML relapse with poor outcomes, creating a need for novel effective therapies. Utilizing the RNA-Seq signature of CRISPR-edited AML cells with mtNPM1 KO, we interrogated the LINCS1000-CMap data set and found several pan-HDAC inhibitors and a WEE1 tyrosine kinase inhibitor among the top expression mimickers (EMs). Additionally, treatment with adavosertib (WEE1 inhibitor) or panobinostat (pan-HDAC inhibitor) exhibited synergistic in vitro lethal activity with MI against AML cells with mtNPM1. Treatment with adavosertib or panobinostat also reduced AML burden and improved survival in AML xenograft models sensitive or resistant to MI.

2023-06-14 | GSE227024 | GEO

Causal linkage of presence of mutant NPM1 to efficacy of novel therapeutic agents against AML cells with mutant NPM1 [RNA-Seq]

2023-06-14 | GSE227022 | GEO

Genome-wide mapping of SET-Nup214, mutant NPM1 (NPM1c), and CRM1-binding sites in human leukemia or mouse ES cell lines

Project description:We used ChIP-seq to examine the genome-wide binding of CRM1, SET-Nup214, and NPM1c in leukemia cell lines. Our analysis revealed that CRM1, SET-Nup214, and NPM1c are preferentially targeted to HOX cluster regions.

2019-11-20 | GSE127983 | GEO

Implications of the miR-10 family in chemotherapy response of NPM1 mutated AML

Project description:Nucleophosmin mutated AML (NPM1mut-AML) patients have a high rate of complete remission (CR) to induction chemotherapy. However, the mechanisms responsible for such effects are unknown. Since miR-10 family members are expressed at high levels in NPM1mut-AML, we evaluated whether these microRNAs could predict chemotherapy response in AML. We found that high baseline miR-10 family expression in 54 untreated cytogenetically heterogeneous AML patients was associated with achieving CR. However, when we included NPM1 mutation status in the multivariable model, there was a significant interaction effect between miR-10a-5p expression and NPM1 mutation status. Similar results were observed when using a second cohort of 183 cytogenetically normal older (age≥60 years) AML patients. Loss and gain of function experiments using miR-10a-5p in cell lines and primary blasts did not demonstrate any effect in apoptosis or cell proliferation at baseline or after chemotherapy. These data support a bystander role for the miR-10 family in NPM1mut-AML.

2014-05-01 | GSE55519 | GEO

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