GEO series
Transcriptomic profiling of bone marrow cells from CML mouse models and newly diagnosed patients treated with SOS1 inhibitor BI-3406 and/or imatinib
GSE303378
Homo sapiens; Mus musculus
Expression profiling by high throughput sequencing
48 samples
Submitted 2026/06/22
Platform GPL24676Platform GPL24247
Summary
Despite the success of BCR-ABL1 tyrosine kinase inhibitors (TKIs) like imatinib in treating chronic myeloid leukemia (CML), therapeutic resistance and disease persistence remain significant challenges. This study investigated the potential of BI-3406, a selective SOS1 inhibitor (a key activator of RAS signaling), either alone or in combination with imatinib. Using preclinical CML models, including transgenic mice and patient samples, it was observed that BI-3406 and imatinib administration were well-tolerated. Although both drugs partially reduced splenomegaly and leukocytosis individually, combination therapy showed a significantly greater therapeutic effect. This combination extended survival, normalized spleen architecture, and sharply reduced leukemic stem and progenitor cells, suggesting a synergistic impact on leukemic burden and stem cell compartments. In vitro assays confirmed that BI-3406 potentiated the cytotoxic effects of imatinib in CML cell lines, increasing apoptosis. Notably, in primary bone marrow cells from patients with the imatinib-resistant T315I mutation, BI-3406 not only synergized with ponatinib but also restored sensitivity to imatinib, offering a potential strategy to overcome drug resistance. RNA sequencing revealed that BI-3406 alone triggered a compensatory anabolic transcriptional program, while imatinib suppressed key proliferative and metabolic pathways. However, combination therapy produced more profound reprogramming, simultaneously reinforcing anti-proliferative effects and activating immune and inflammatory pathways. These conserved effects across murine and human samples support the translational potential of this dual-targeting strategy. In conclusion, SOS1 inhibition with BI-3406, in combination with TKIs, dismantles oncogenic signaling, suppresses leukemic stemness, and reprograms the immune microenvironment. This dual-targeting approach holds promise as a novel therapeutic strategy to enhance TKI efficacy and overcome resistance in CML.
This dataset
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Direct links to NCBI, no account and no request form: the whole study as GSE303378_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 48 samples. Raw sequencing reads are also available from ENA.
Also filed as BioProject PRJNA1294971 and SRA study SRP602785. Searching any of these in the dataset finder brings you back here.
Study design
7 conditions, mostly with about 4 replicates each
Bone marrow, Mouse, BCR-ABL–, untreated, ×4
Bone marrow, Mouse, BCR-ABL+, vehicle, ×4
Bone marrow, Mouse, BCR-ABL+, IMA, ×4
Bone marrow, Mouse, BCR-ABL+, BI3406, ×4
Bone marrow, Mouse, BCR-ABL+, IMA+BI3406, ×4
Bone marrow, Mouse, BCR-ABL+, SOS1KO, ×4
Bone marrow, Mouse, BCR-ABL+, SOS1KO+IMA, ×4
Bone marrow MNCs, Human, Patient 1, untreated ×1
+11 more
Supports a case/control comparison: 9 samples read as cases, 4 as controls.
7 replicated groups read from the first 40 of 48 sample titles; they account for 28 of them. Check it against the sample list below before relying on it.
Samples in this study
0 selected
- GSM9124786 Bone marrow, Mouse, BCR-ABL–, untreated, rep1
- GSM9124787 Bone marrow, Mouse, BCR-ABL–, untreated, rep2
- GSM9124788 Bone marrow, Mouse, BCR-ABL–, untreated, rep3
- GSM9124789 Bone marrow, Mouse, BCR-ABL–, untreated, rep4
- GSM9124790 Bone marrow, Mouse, BCR-ABL+, vehicle, rep1
- GSM9124791 Bone marrow, Mouse, BCR-ABL+, vehicle, rep2
- GSM9124792 Bone marrow, Mouse, BCR-ABL+, vehicle, rep3
- GSM9124793 Bone marrow, Mouse, BCR-ABL+, vehicle, rep4
- GSM9124794 Bone marrow, Mouse, BCR-ABL+, IMA, rep1
- GSM9124795 Bone marrow, Mouse, BCR-ABL+, IMA, rep2
- GSM9124796 Bone marrow, Mouse, BCR-ABL+, IMA, rep3
- GSM9124797 Bone marrow, Mouse, BCR-ABL+, IMA, rep4
- GSM9124798 Bone marrow, Mouse, BCR-ABL+, BI3406, rep1
- GSM9124799 Bone marrow, Mouse, BCR-ABL+, BI3406, rep2
- GSM9124800 Bone marrow, Mouse, BCR-ABL+, BI3406, rep3
- GSM9124801 Bone marrow, Mouse, BCR-ABL+, BI3406, rep4
- GSM9124802 Bone marrow, Mouse, BCR-ABL+, IMA+BI3406, rep1
- GSM9124803 Bone marrow, Mouse, BCR-ABL+, IMA+BI3406, rep2
- GSM9124804 Bone marrow, Mouse, BCR-ABL+, IMA+BI3406, rep3
- GSM9124805 Bone marrow, Mouse, BCR-ABL+, IMA+BI3406, rep4
- GSM9124806 Bone marrow, Mouse, BCR-ABL+, SOS1KO, rep1
- GSM9124807 Bone marrow, Mouse, BCR-ABL+, SOS1KO, rep2
- GSM9124808 Bone marrow, Mouse, BCR-ABL+, SOS1KO, rep3
- GSM9124809 Bone marrow, Mouse, BCR-ABL+, SOS1KO, rep4
- GSM9124810 Bone marrow, Mouse, BCR-ABL+, SOS1KO+IMA, rep1
- GSM9124811 Bone marrow, Mouse, BCR-ABL+, SOS1KO+IMA, rep2
- GSM9124812 Bone marrow, Mouse, BCR-ABL+, SOS1KO+IMA, rep3
- GSM9124813 Bone marrow, Mouse, BCR-ABL+, SOS1KO+IMA, rep4
- GSM9124814 Bone marrow MNCs, Human, Patient 1, untreated
- GSM9124815 Bone marrow MNCs, Human, Patient 1, IMA
- GSM9124816 Bone marrow MNCs, Human, Patient 1, BI3406
- GSM9124817 Bone marrow MNCs, Human, Patient 1, IMA+BI3406
- GSM9124818 Bone marrow MNCs, Human, Patient 2, untreated
- GSM9124819 Bone marrow MNCs, Human, Patient 2, IMA
- GSM9124820 Bone marrow MNCs, Human, Patient 2, BI3406
- GSM9124821 Bone marrow MNCs, Human, Patient 2, IMA+BI3406
- GSM9124822 Bone marrow MNCs, Human, Patient 3, untreated
- GSM9124823 Bone marrow MNCs, Human, Patient 3, IMA
- GSM9124824 Bone marrow MNCs, Human, Patient 3, BI3406
- GSM9124825 Bone marrow MNCs, Human, Patient 3, IMA+BI3406
+ 8 more — browse all 48 samples with per-sample file links →
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