The Oncogenic Potential of the Homeobox Gene Cdx2 Is Depending on the MAPK Pathway and Can Be Antagonized by the MEK1/2 Inhibitor PD98059 in a Mouse Model of t(12;13)(p13;q12) Positive AML.
Bibliographic record
Abstract
Abstract In AML the translocation t(12;13)(p13;q12) results in the ectopic expression of the homeobox gene Cdx2 and the expression of the ETV6-CDX2 fusion. We have recently shown that myeloid leukemogenesis is induced by the ectopic expression of the proto-oncogene Cdx2 and not by the ETV6-CDX2 fusion gene in a murine model of t(12;13) AML. To characterize the contribution of different Cdx2 motifs to the transforming capacity of the gene we generated different mutants, inactivating the DNA binding homeodomain (N51S-Cdx2), or the PBX1-interacting motif (W167A-Cdx2), or deleting the N-terminal portion of Cdx2 (N-Cdx2). Expression of Cdx2 and the different mutants were induced in primary murine bone marrow cells by retroviral gene transfer, using an MSCV based retroviral construct with an IRES-YFP cassette. Expression of Cdx2 and the W167A-Cdx2 mutant significantly increased primary colony formation (3-fold) (n=3;p<0.001) with a higher number of CFU-G/GM colonies (p<0.015). Furthermore, both constructs enhanced the replating capacity of clonogenic progenitors with an 80-100fold increase in secondary colonies (p<0.005). In addition, both constructs induced the outgrowth of blast colonies (2700fold; p<0.02). In contrast, cells transduced with N51S-Cdx2 and N-Cdx2 lost their clonogenic potential after replating. In vivo all mice transplanted with cells expressing Cdx2 or the W167A-Cdx2 mutant developed transplantable AML. However, in Cdx2 leukemic mice > 90% of the cells co-expressed Gr-1+ and Mac1+, whereas in W167A mice 40% of the leukemic population were Gr-1+ only. The N51S mutant induced a distinct leukemia phenotype with 90 % Gr-1+/c-Kit+. We extended structure-function analyses, inactivating the phosphorylation site (S60) in the Cdx2 transactivation domain, previously shown to be regulated by the MAPK family. We confirmed that oncogenic Cdx2 is phophorylated at the N-terminal in primary BM cells by Western blotting using a P-Cdx2-S60 specific antibody. S60 position mutation slightly reduced the hematopoietic activity of wild-type Cdx2. Incubation with the MEK1 inhibitor PD98059 inhibited phosphorylation, decreased the frequency of CFU-S 8fold (n=7; p<0.001) and blocked growth of leukemic Cdx2 transfected blasts in vitro. In contrast, the p38 inhibitor SB2059 did not prevent phosphorylation and was unable to antagonize Cdx2 induced transformation. These data demonstrate that the transforming activity of Cdx2 and the phenotype of Cdx2 induced leukemias is depending on the functional integrity of distinct Cdx2 domains. Furthermore, our data link the oncogenic potential of Cdx2 directly to the MAPK signaling, opening the possibility to counteract Cdx2 associated leukemogenesis by kinase inhibitors.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| 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) | 0.002 | 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 source (direct Gemma or distilled Codex), 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".