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Inhibition of MEK and ATR induces synergistic killing of a Mll-Af4 B-ALL model harboring activated Ras mutation

ABSTRACT: Infant B-acute lymphoblastic leukemias (B-ALL) that harbor MLL-AF4 rearrangements are associated with a poor prognosis. One important obstacle to progress for this patient population is the lack of models that faithfully recapitulate the short latency and aggressiveness of this disease. While current mouse models of Mll-Af4 can generate acute leukemia, not all are lymphoid, and the long latency to disease does not reflect what is seen in patients. Recent whole genome sequencing of MLL-AF4 B-ALL samples revealed a high frequency of mutations in proto-oncogenes involved in signaling pathways. Here, we demonstrate that the expression of activating mutant N-RasG12D cooperates with Mll-Af4 to generate a highly aggressive, serially transplantable B-ALL in mice. We used our novel mouse model to test the sensitivity of Mll-Af4/N-RasG12D leukemia to small molecule inhibitors, and found that dual targeting of the downstream effectors of Ras and the DNA damage response pathway through ATR inhibition induced long-term durable responses in both mouse and patient derived xenografts with both mutations in vivo. Our studies suggest that this mouse model of Mll-Af4/N-Ras B-ALL is not only a powerful tool to explore the molecular and genetic pathogenesis of this disease subtype, but also is an important preclinical discovery platform for novel therapeutics that might be used to treat patients with this disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE89560 | GEO | 2018/11/28

REPOSITORIES: GEO

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The RNA binding protein IGF2BP3 is required MLL-AF4 mediated leukemogenesis

Project description:In our study, we found that MLL-AF4 transcriptionally induces IGF2BP3 and is required for MLL-Af4 mediated leukemogenesis. Deletion of murine Igf2bp3 significantly increased the survival of mice with MLL-Af4 driven leukemia and greatly attenuated disease. Furthermore, Igf2bp3 was necessary for the development of and the self-renewal capacity of MLL-Af4 leukemic initiating cells. eCLIP and transcriptome analysis of MLL-Af4 transformed stem and progenitor cells and primary cells from MLL-Af4 leukemic mice revealed an IGF2BP3-regulated post-transcriptional operon governing tumor cell survival and proliferation. Critical mRNA targets include the Hoxa locus and numerous genes within the Ras signaling pathway. Together, our findings show that IGF2BP3 is an essential positive regulator of MLL-AF4 mediated leukemogenesis and is a potential therapeutic target in this disease.

2021-08-11 | GSE156115 | GEO

Gene Expression Profiling of the MLL-AF4 and Flt3 tyrosine kinase domain (TKD) genes in 32Dc cell

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2009-03-31 | E-GEOD-14236 | biostudies-arrayexpress

Remodeling of the DNA methylation landscape of CD34+ cells from fetal liver / cord blood upon upon CRISPR mediated t(4:11) rearrangements.

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Expression and ChIP-chip data from REH and SEM leukemia cell lines

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Project description:We studied the KRAS and NRAS mutational status in pediatric MLL-AF4+ leukemia patients by means of ultra deep amplicon sequencing. The gene expression profiles of RAS wild type and RAS mutated patients were investigated by gene expression analysis. We showed that mutated patients were characterized by a RAS related expression signature.

2016-10-04 | GSE77416 | GEO

Gene Expression Profiling of the MLL-AF4 and Flt3 tyrosine kinase domain (TKD) genes in 32Dc cell

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Expression, ChIP-chip, and ChIP-Seq data from REH and SEM leukemia cell lines [ChIP-Seq]

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2012-05-31 | E-GEOD-38338 | biostudies-arrayexpress

A novel human fetal model of infant ALL reveals a link between MLL-AF4, PAF1 and increased H3K79me2/3 [RNA-seq]

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2021-10-25 | GSE162032 | GEO

Gene expression profile of bone marrow cells from leukemic mice by transduction of synonymous mutant of MLL-AF4

Project description:The establishment of a murine disease model of MLL-AF4 via retroviral transduction has been difficult due to a lack of understanding of its unknown regulatory mechanisms. We showed that MLL-AF4 protein is post-transcriptionally regulated, and its synonymous mutant is able to induce myeloid leukemia by retroviral transduction. To validate synonymous mutant of MLL-AF4 is phenotypically similar to the MLL-mAf4, we analyzed the gene expression profiles by RNA-seq.

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