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| Status |
Public on Dec 01, 2020 |
| Title |
A hotspot mutation p.L162R in IKZF3 drives leukemogenesis via transcriptional dysregulation |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
IKZF3 encodes an IKAROS Family transcription factor and has been recently identified as a novel mutated gene in chronic lymphocytic leukemia (CLL), with all mutations occurring at a single hotspot (L162R), located within the DNA binding domain of the protein. Here we show that B cell-restricted conditional knock-in of this mutation skews B cells development and induces CLL-like disease in elderly mice (30% penetrance), confirming its role as a CLL driver. Furthermore, this mutation alters the DNA binding specificity and target selection of IKZ3, leading to overexpression of BCR/NF-?B signaling genes and hyperactivation of these pathways. Likewise, we find an upregulated BCR signaling signature in human CLLs with IKZF3-L162R. Our studies highlight a novel mechanism by which a CLL driver activates the critical oncogenic BCR/NF-?B signaling axis in CLL
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| Overall design |
We generated a novel conditional knock-in murine model with B-cell restricted expression of the Ikzf3-L161R mutation. RNA-seq, ChIP-seq and ATAC-seq were performed in CLL cells with Ikzf3 mutation, non-CLL cells from the same mice with the mutation, as well as WT normal B cells.
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| Contributor(s) |
Yin S, Lazarian G, Wu CJ |
| Citation missing |
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| |
| Submission date |
Jan 15, 2020 |
| Last update date |
Dec 04, 2020 |
| Contact name |
Catherine Wu |
| Organization name |
Dana-Farber Cancer Institute
|
| Lab |
Wu lab
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| Street address |
450 Brookline Avenue
|
| City |
Boston |
| State/province |
MA |
| ZIP/Postal code |
02115 |
| Country |
USA |
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| Platforms (2) |
| GPL9185 |
Illumina Genome Analyzer (Mus musculus) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (30)
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| Relations |
| BioProject |
PRJNA601427 |
| SRA |
SRP242039 |
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