Identification and characterization of the Icsbp1R294C mutation in BXH-2 mice responsible for their unique susceptibility to intracellular pathogens and their chronic myeloid leukemia-like syndrome
Bibliographic record
Abstract
While studying the unique Nramp1 (Slcl1a1)-independent susceptibility of BXH-2 mice to Mycobacterium bovis (BCG) infection, we noted that these mice develop splenomegaly associated with important infiltration of Mac-1+/GR-1+ (macrophage antigen-1 +/granulocyte differentiation antigen 1+) granulocyte precursors in spleen, lymph nodes and bone marrow resembling a myeloproliferative syndrome. This syndrome was subsequently found to be independent of the BCG infection. Segregation analyses revealed that the myeloproliferative syndrome was controlled by a single recessive locus (Myls) mapping to a 9 megabases (Mb) region of chromosome 8. Myls contained one of the two replication-defective proviruses (Emv2) integrated into BXH-2 genome, and thought to play a role in generating the replication competent B-tropic ecotropic munne leukemia virus (MuLV) known to cause clonal tumours in BXH-2 mice. By narrowing down the Myls interval to 2 Mb, we could exclude Emv2 as a potential candidate for Myls. However, several other candidates remained, among which the interferon consensus sequence binding protein 1 (Icsbp1) gene. We showed that BXH-2 mice carry a mutation (915 C to T) resulting in an arginine-to-cysteine substitution at position 294 within the transactivation domain of the Icsbp1 protein. We found that Icsbp1C294 behaves as a hypomorphic allele which appears to have a threshold effect on maturation of the myeloid lineage, as well as pleiotropic consequences on resistance to different types of infectious agents including Mycobacterium bovis (BCG). Our results suggest a two-step mutagenic model in which first, inactivation of Icsbp1 predisposes to myeloproliferation and immunodeficiency and favours the production of retroviruses. Then, subsequent insertional mutagenesis of oncogenes or tumour suppressors by the retrovirus results in clonal expansion of leukemic cells characteristic of BXH-2 mice.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".