LMO2 Regulates DNA Replication in Hematopoietic Cells
Bibliographic record
Abstract
Abstract Oncogenic transcription factors are major drivers in acute leukemias. These oncogenes are believed to subvert normal cell identity via the establishment of gene expression programs that dictate cell differentiation and growth. The LMO2 oncogene, which is commonly activated in T-cell acute lymphoblastic leukemia (T-ALL), has a well-established function in transcription regulation. We and others previously demonstrated that LMO1 or LMO2 collaborate with the SCL transcription factor to activate a self-renewal program that converts non self-renewing progenitors into pre-leukemic stem cells. Here we demonstrate a non-transcriptional role of LMO2 in controlling cell fate by directly promoting DNA replication, a hitherto unrecognized mechanism that might also account for its oncogenic properties. To address the question whether LMO2 controls other functions via protein-protein interactions, we performed a proteome-wide screen for LMO2 interaction partners in Kit+ Lin- cells. In addition to known LMO2-interacting proteins such as LDB1 and to proteins associated with transcription, we unexpectedly identified new interactions with three essential DNA replication enzymes, namely minichromosome 6 (MCM6), DNA polymerase delta (POLD1) and DNA primase (PRIM1). First, we show that in Kit+ hematopoietic cells (TF-1), all components of the pre-replication complex co-immunoprecipitate with LMO2 but not with SCL, suggesting a novel SCL-independent function. Second, LMO2 is recruited to DNA replication origins in these cells together with MCM5. Third, tethering LMO2 to synthetic DNA sequences is sufficient to transform these into origins of replication. Indeed, we show by DNA capture that LMO2 fused to the DNA binding domain of GAL4 is sufficient to recruit DNA replication proteins to GAL4 binding sites on DNA. In vivo, this recruitment is sufficient to drive DNA replication in a manner which is dependent on the integrity of the GAL4 binding sites. These results provide unambiguous evidence for a role of LMO2 in directly controlling DNA replication. Cell cycle and cell differentiation are tightly coordinated during normal hematopoiesis, both during erythroid differentiation and during thymocyte development. We next addressed the functional importance of LMO2 in these two lineages. Erythroid cell differentiation proceeds through different stages from the CD71+Ter119- to the CD71-Ter119+. These stages are also distinguishable by morphological criteria. We observe that LMO2 protein levels directly correlate with the proportion of cells in S phase, i.e. both LMO2 levels and the proportions of cycling cells decrease with terminal erythroid differentiation. Strikingly, lowering LMO2 levels in fetal liver erythroid progenitors via shRNAs decreases the proportion of cells in S phase and arrests Epo-dependent cell growth. Despite a drastic decrease in the numbers of erythroid precursors, these cells differentiate readily to the CD71-Ter119+ stage. Therefore, LMO2 levels dictate cell fate in the erythroid lineage, by favoring DNA replication at the expense of terminal maturation. Conversely, ectopic expression in thymocytes induces DNA replication and drives cells into cell cycle, causing differentiation blockade. Our results define a novel role for the oncogenic transcription factor LMO2 in directly promoting DNA synthesis. To our knowledge, this is the first evidence for a non-transcriptional function of the LMO2 oncogene that drives cell cycle at the expense of differentiation, favouring progenitor cell expansion in the thymus, and causing T-ALL when ectopically expressed in the T lineage. We propose that the non-transcriptional control of DNA replication uncovered here for LMO2 may be a more common function of oncogenic transcription factors than previously appreciated. Disclosures No relevant conflicts of interest to declare.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
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".