Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

HOXA9 cooperates with activated JAK/STAT signaling to drive leukemia development

ABSTRACT: Leukemia is caused by the accumulation of multiple genomic lesions in hematopoietic precursor cells. However, how these events cooperate during oncogenic transformation remains poorly understood. We studied the cooperation between activated JAK3/STAT5 signaling and HOXA9 overexpression, two events identified as significantly co-occuring in T-cell acute lymphoblastic leukemia. Expression of mutant JAK3 and HOXA9 led to a rapid development of leukemia originating from multipotent or lymphoid-committed progenitors, with a significant decrease in disease latency compared to JAK3 or HOXA9 alone. Integrated RNA-seq, ChIP-seq and ATAC-seq revealed that STAT5 and HOXA9 have co-occupancy across the genome resulting in enhanced STAT5 transcriptional activity and ectopic activation of Fos/Jun (AP-1). Our data suggest that oncogenic transcription factors such as HOXA9 provide a fertile ground for specific signaling pathways to thrive, explaining why JAK/STAT pathway mutations accumulate in HOXA9 expressing cells.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE109653 | GEO | 2018/01/26

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

HOXA9 cooperates with activated JAK/STAT signaling to drive leukemia development

Project description:HOXA9 cooperates with activated JAK/STAT signaling to drive leukemia development

| PRJNA431601 | ENA

Expression data from murine hematopoietic cells expressing BCR-ABL alone, NUP98-HOXA9 alone, BCR-ABL and NUP98-HOXA9, or null for both oncogenes

Project description:Leukemia is a complex malignancy with hundreds of distinct mutations associated with disease development. Studies have shown that oncogenes cooperate to promote leukemia transformation, however, the downstream effectors of this cooperation are largely unknown. Using a genetically defined mouse model of acute leuekmia, we investigated the regulated of genes downstream of the cooperative oncogenic interaction between BCR-ABL and NUP98-HOXA9 and identified a unique gene signature abberrantly expression in leukemia. Total RNA was isolated from hematopoietic cells transduced with BCR-ABL and Nup98-HOXA9 retroviruses and transplanted into recipient mice. Bone marrow cells were purified by GFP (BCR-ABL) and YFP (NUP98-HOXA9) using FACS.

2012-05-10 | E-GEOD-37907 | biostudies-arrayexpress

Gene expression of Kit225 cells upon NC1153 treatment

Project description:NC1153 was shown to inhibit JAK3 tyrosine kinase. Lymphocytes survival depends on the integrity of STAT5, the primary downstream target of JAK3. In this study microarrays were used to test the effect of a JAK3 inhibitor, NC1153, on the gene expression profile of a human leukemia cell line. Kit225 human leukemia cells were treated with NC1153 or DMSO (vehicle) for 12 h then harvested for RNA isolation.

2010-07-08 | E-GEOD-17007 | biostudies-arrayexpress

Expression data from murine hematopoietic cells expressing BCR-ABL alone, NUP98-HOXA9 alone, BCR-ABL and NUP98-HOXA9, or null for both oncogenes

2012-05-11 | GSE37907 | GEO

Gene expression of Kit225 cells upon NC1153 treatment

2010-07-08 | GSE17007 | GEO

Effect of loss of Jmjd1c on Hoxa9/Meis1 leukemia

Project description:Analysis of gene expression profile of Hoxa9/Meis1 leukemia cells 6 days after loss of Jmjd1c. Loss of Jmjd1c induces differentiation and Hoxa9/Meis1 leukemia cells. These results provide insight into the role of Jmjd1c in AML with elelvated expression of Hoxa9.

2016-06-09 | GSE75580 | GEO

Evaluation of the NUP98-HOXA9 role as oncogenic transcription factor

Project description:To study the oncogenic mechanism triggered by the leukemic fusion protein NUP98-HOXA9, we cloned the cDNA of NUP98-HOXA9 into a retroviral vector (pMSCV-IRES-GFP) and efficiently transduced the HEK293FT human cell line. We performed a ChIP-seq analysis to identify the DNA binding sites of NUP98-HOXA9. These results allowed us to demonstrate that NUP98-HOXA9 regulates the expression of genes involved in the development of Acute Myeloid Leukemia by directly interacting with their enhancer regions. We further investigated the functional contribution to the DNA binding profile of the two moieties that compose the fusion protein. We cloned the coding region of HOXA9 wt and NUP98 wt in the same retroviral vector, established two new cellular models, 293FT-HOXA9 and 293FT-NUP98, and performed separate ChIP-seq analyses. We demonstrated that both moieties contribute importantly to the regulation of the target genes.

2016-12-31 | GSE62586 | GEO

Hoxa9 and Meis1 cooperatively induce addiction to Syk signaling by suppressing miR-146a in acute myeloid leukemia

Project description:The transcription factor Meis1 drives myeloid leukemogenesis in the context of Hox gene overexpression but is currently considered undruggable. We therefore investigated whether myeloid progenitor cells transformed by Hoxa9 and Meis1 become addicted to targetable signaling pathways. A comprehensive (phospho)proteomic analysis revealed that Meis1 increased Syk protein expression and activity. Syk upregulation occurs through a Meis1-dependent feed-forward loop. By dissecting this loop, we show that Syk is a direct target of miR-146a, whose expression is indirectly regulated by Meis1 through the transcription factor PU.1. In the context of Hoxa9 overexpression, Syk induces Meis1, recapitulating several leukemogenic features of Hoxa9/Meis1-driven leukemia. Finally, we show that Syk inhibition disrupts the identified regulatory loop, prolonging survival of mice with Hoxa9/Meis1-driven leukemia.

2017-06-14 | PXD004192 | Pride

MLL is essential for NUP98-HOXA9-induced leukemia

Project description:Rearrangements involving the NUP98 gene resulting in fusions to several partner genes occur in acute myeloid leukemia and myelodysplastic syndromes. This study demonstrates that the second FG repeat domain of the NUP98 moiety of the NUP98-HOXA9 fusion protein is important for its cell immortalization and leukemogenesis activities. We demonstrate that NUP98-HOXA9 interacts with MLL via this FG repeat domain and that, in the absence of MLL, NUP98-HOXA9-induced cell immortalization and leukemogenesis are severely inhibited. Molecular analyses indicate that MLL is important for the recruitment of NUP98-HOXA9 to the HOXA locus and for NUP98-HOXA9-induced HOXA gene expression. Our data indicate that MLL is crucial for NUP98-HOXA9 leukemia initiation.

2017-02-28 | GSE93923 | GEO

Functional Interrogation of HOXA9 Regulome in Leukemia via Endogenous Reporter-based CRISPR/Cas9 screen

Project description:Aberrant HOXA9 expression is a hallmark of most aggressive acute leukemias, including a vast majority of human acute myeloid leukemia (AML) and subtypes of acute lymphoblastic leukemia (ALL). HOXA9 overexpression not only predicts poor patient diagnosis and outcome, but also plays critical roles in leukemia transformation and maintenance. Besides in few clinical cases as a translocation partner, HOXA9 gene generally shows lower frequencies of somatic mutations and is rarely amplified, indicating that transcriptional and epigenetic regulatory mechanisms might be predominantly utilized. However, our current understanding on the upstream regulation of HOXA9 in acute leukemia is still very limited, hindering development of effective methods to treat leukemia driven by aberrant HOXA9 expression. To mitigate these challenges, we have established the first HOXA9 endogenous reporter in an MLL-rearranged leukemia cell line to faithfully dictate HOXA9 expression by mCherry. By utilizing the reporter cell line and CRISPR/Cas9 genome editing tools, we have exploited comprehensive loss-of-function screenings to systematically discover novel transcription factors controlling HOXA9 expression. USF2 was discovered as a novel regulator of HOXA9 that directly binds to HOXA9’s promoter. USF2 depletion significantly down-regulated HOXA9 expression. Notably, in patients with MLL-rearranged B-ALL, transcriptional expression of USF2 and that of HOXA9 were positively correlated. In contrast, chromatin looping factor CTCF was dispensable for controlling HOXA9 expression in MLL-rearranged SEM cells. Collectively, these studies have functionally interrogated the regulome of HOXA9 and advance our understanding of the molecular regulation network in HOXA9-driven leukemia.

2020-10-30 | GSE140664 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data