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Overexpression of the signaling-coordinator GAB2 can play an important role in Acute Myeloid Leukemia progression

ABSTRACT: Label free quantification (LFQ) proteomics experimental data from a study of murine acute myeloid leukemia (AML) that spontaneously develops in mice with Dnmt3aR878H/+ x Npm1cA/+ bone marrow. These mice spontaneously develop myelomonocytic AML in 6-15 months. We characterized pre-leukemic bone marrow samples, and 11 independent spontaneous AMLs that developed in these doubly-mutant mice ("mAML1-11").10 of 11 AMLs contained an amplification of murine chromosome 7 (chr7), usually as the only structural variant. Furthermore, we identified two non-leukemic mice where whole genome sequencing revealed amplification of chromosome 7 (+7) and no other cooperating mutations in identifiable driver genes (pre-tumor, +7 only). One of these clonal expansions was tested twice in secondary transplant assays, and did not commonly yield fatal disease when transplanted into recipients, suggesting that +7 is an intermediate step in AML progression. Further experiments identified Gab2 as an important gene on chromosome 7 for AML pathogenesis in this model. Retroviral overexpression of Gab2 in Dnmt3aR878H/+ x Npm1cA/+ bone marrow led to expansion of bone marrow cells both in vitro and in vivo in transplanted, recipient mice, as well as to accelerated development of AML; the resulting AML samples are called GAB2 mAML in this dataset. Measurements were performed from bulk bone marrow of mice. Data can be explored further at mAML.leylab.org. Note that data uploaded here were analyzed using the publicly available FragPipe software, with full workflow details available for download. In the JCI publication in press and on the mAML.leylab.org website, data were analyzed as described in the methods section, with expected slight variation in the protein quantification results. The conclusions presented in the publication are supported by both analyses.

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Timothy J. Ley

PROVIDER: MSV000098728 | MassIVE | Tue Aug 05 09:36:00 BST 2025

REPOSITORIES: MassIVE

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Project description:Acute Myeloid Leukemia (AML) is characterized by the clonal expansion of immature myeloblasts originating from leukemic stem cells (LSCs) niched within the bone marrow. Bone marrow stromal cells (BMSC) and tumor-stroma interactions play a prominent role in the evolution of this disease. BMSC-mediated protection of leukemic cells involves several mechanisms, including interactions between adhesion molecules, the secretion of cytokines/chemokines and the release of extracellular vesicles produced by the surrounding non-haemopoietic BM cells. Recent studies even suggest that autophagy in the tumor stroma is associated with leukemia progression, survival and resistance. Thus, it seems widely evident that the microenvironment profile affects the prognosis and influences the efficacy of anti-cancer therapies. Yet, although widely explored, the crosstalk between leukemic and stromal cells remains poorly understood. Syntenin (directing endocytosed SDC and receptor cargo back to cell surfaces and/or to endosomal intraluminal vesicles and exosomes) is known to coordinate inter-cellular communications. Using syntenin-knockout mice, we aimed to clarify the role of environmental-syntenin in the progression of AML, a disease in which the role of (tumor/host) syntenin was not yet investigated. To address the role of host-syntenin in AML, I extensively used the mouse FLB1 AML-like model (generous gift of O. Herault, Tours). Strikingly, FLB1 cells show a marked gain in aggressiveness when serially transplanted a syntenin-KO host. This aggressive behavior is cell-autonomous, as not reversed by back transplantation into WT hosts. Moreover, ‘aggressive’ FLB1 blasts, raised by education in a syntenin-negative in vivo background, are able to survive and grow in vitro in the absence of stroma, suggesting the cell-autonomous activation of survival pathways. Surprisingly, this gain of aggressiveness is not accompanied by a noticeable morphotypic or transcriptomic signature. However using quantitative proteomics we highlighted altered mRNA translational control. Aggressive FLB1 show a significant up-regulation of several factors, but most marked for EEF1A2, previously shown to have pro-oncogenic activities in various cancers..Globally, these findings are also consistent with the emerging notion that altered mRNA translational control is a critical factor in cancer development and progression.

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Overexpression of the signaling-coordinator GAB2 can play an important role in Acute Myeloid Leukemia progression

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