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Cleavage Under Targets & Release Using Nuclease (CUT&RUN) of monosomy 7 compared to normal karyotype control

ABSTRACT: Monosomy 7 is one of the most frequent aneuploidies in myeloid malignancies, associated to heterogeneous phenotypes. Its poor prognosis differentiates it from aberrations leading to partial/complete loss of 7q region. Underlying pathogenic mechanisms are still undetermined. We performed a comprehensive epi-genomic study of karyotypically isolated monosomy 7 in adult Myelodysplastic Syndromes/Acute Myeloid Leukemias.

ORGANISM(S): Homo sapiens

PROVIDER: GSE318557 | GEO | 2026/03/26

REPOSITORIES: GEO

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Affymetrix SNP array data for adult Myelodysplastic Syndromes (MDS)/Acute Myeloid Leukemia (AML) with isolated monosomy 7

Project description:Monosomy 7 is one of the most frequent aneuploidies in myeloid malignancies, associated to heterogeneous phenotypes. Its poor prognosis differentiates it from aberrations leading to partial/complete loss of 7q region. Underlying pathogenic mechanisms are still undetermined. We performed a comprehensive epi-genomic study of karyotypically isolated monosomy 7 in adult Myelodysplastic Syndromes/Acute Myeloid Leukemias.

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Muscle transcriptome analysis of mouse models of partial trisomy and monosomy 21

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Project description:Monosomy 7 and del(7q) are among the most common and poorly understood genetic alterations in myelodysplastic neoplasms and acute myeloid leukemia. Chromosome band 7q22 is a minimally deleted segment in myeloid malignancies with a del(7q). However, the rarity of “second hit” mutations supports the idea that del(7q22) represents a contiguous gene syndrome. We generated mice harboring a 1.5 Mb germline deletion of chromosome band 5G2 syntenic to human 7q22 that removes Cux1 and 27 additional genes. Hematopoiesis is perturbed in 5G2+/del mice but they do not spontaneously develop hematologic disease. Whereas alkylator exposure modestly accelerated tumor development, the 5G2 deletion did not cooperate with KrasG12D, NrasG12D, or the MOL4070LTR retrovirus in leukemogenesis. 5G2+/del mice are a novel platform for interrogating the role of hemopoietic stem cell attrition/stress, cooperating mutations, genotoxins, and inflammation in myeloid malignancies characterized by monosomy 7/del(7q).

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Cleavage Under Targets & Release Using Nuclease (CUT&RUN) of monosomy 7 compared to normal karyotype control

Project description:Cleavage Under Targets & Release Using Nuclease (CUT&RUN) of monosomy 7 compared to normal karyotype control

| PRJNA1419218 | ENA

CUX1 deficiency potentiates RAS signaling to drive malignancy

Project description:-7/del(7q) is genetic event prevalent in high-risk myeloid neoplasms. For reasons that are unclear, gain-of-function mutations in the RAS pathway frequently co-occur with monosomy 7. Here we identify a genetic interaction between RAS and the 7q-encoded transcription factor, CUX1. Concomitant mutations in RAS genes and CUX1 are wide-spread across tumor types, suggesting cooperativity in tumorigenesis. To test this, we generated mice with oncogenic NrasG12D and Cux1 knockdown. Double mutant mice developed myeloid malignancies with higher penetrance and faster onset than either single allele alone, with leukemic transformation in one third of cases. Oncogenic RAS imparts increased self-renewal on CUX1-deficient hematopoietic stem and progenitor cells (HSPCs). Reciprocally, CUX1 knockdown amplifies RAS signaling through decreased transcriptional expression of negative regulators of RAS and PI3K signaling. Accordingly, NrasG12D;Cux1-knockdown HSPCs have heighted growth factor-sensitivity and downstream RAS pathway activation. Double mutant HSPCs were responsive to PIK3 or MEK inhibition, suggesting that these may be promising therapeutic targets in patients with 7/del(7q) malignancies. Our results implicate the loss of CUX1 as the underlying explanation for the association of -7/del(7q) with oncogenic RAS. Furthermore, we report the unexpected convergence of an oncogene and tumor suppressor gene on the same pathway.

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Clinical Utility of Targeted Next-Generation Sequencing Assay to Detect Copy Number Variants in Myeloid Malignancies: Is It Ready for Prime Time?

Project description:Genetic abnormalities including copy number variants (CNVs, such as gains and losses), and gene mutations are important for diagnosis and treatment of myeloid malignances. In a routine clinical setting, somatic gene mutations are detected by targeted next generation sequencing (NGS), but CNVs are commonly detected by conventional chromosome analysis and fluorescence in situ hybridization (FISH). The aim of this proof-of-principle study was to investigate the feasibility of using a targeted NGS assay to simultaneously detect not only somatic mutations, but also CNVs. Here, we sequenced 406 consecutive patients with myeloid malignancies and performed a head-to-head comparison with the results from conventional clinical assays including conventional chromosome analysis and myeloid FISH to detect CNVs. The targeted NGS assay revealed all 120 CNVs detected by myeloid FISH panel including monosomy 5/5q deletions, monosomy 7/7q deletions, trisomy 8, and 20q deletions. Furthermore, the targeted NGS assay also detected 605 CNVs outsides targeted regions of the myeloid FISH panel, which were revealed by conventional cytogenetic testing. The targeted NGS assay achieved 100% concordance with the myeloid FISH for detection of these common myeloid CNVs, with a high clinical sensitivity (> 99%) and specificity (>99%). The lower limit of detection by the myeloid FISH and the targeted NGS assay was similar and was generally 5% variant allele fraction for DNA. This proof-of-principle study demonstrated that the targeted NGS assay can simultaneously detect both common myeloid CNVs and somatic mutations, which can provide more comprehensive genetic profiling for patients with myeloid malignancies using a single assay.

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