Expression of MLL Fusion Genes in Human Hematopoietic Cells Is Sufficient To Induce Both Acute Lymphoid and Acute Myeloid Leukemia In Vivo.
Bibliographic record
Abstract
Abstract Malignant transformation involves the acquisition of a series of genetic and epigenetic changes that subvert the normal cellular developmental program and result in the generation of a neoplastic clone with deregulated growth properties. However, in some instances, acquisition of a single oncogenic hit may be sufficient to induce a clinical disease. Studies on identical twins that developed acute leukemias during their childhood have clearly demonstrated that all oncogenes are not equal with some exhibiting greater potency than others. MLL translocations, the most frequent cause of infant leukemias, occur in utero and can be identified on Guthrie cards. Identical twins have a concordance rate near 100% with a short latency, a near synchronous diagnosis and a very poor prognosis, suggesting that MLL leukemias are a single hit disease. In order to test the effects and potency of MLL fusion genes in human hematopoietic cells, we conducted a series of in vivo experiments using retroviruses encoding either MLL-ENL or MLL-AF9. Lineage-depleted cord blood cells were transduced with these viruses then injected into sub-lethally irradiated NOD/SCID mice. 15 out of 16 MLL-ENL mice developed an aggressive human pro-B acute lymphoblastic leukemia (ALL) characterized by the extensive accumulation of immature B cells in the bone marrow and organs in less than 18 weeks. 5 out of 12 MLL-AF9 mice developed the same B-precursor ALL while 2 others developed myelomonocytic leukemia. 5 of the 6 mice injected with MLL-transduced cells did not show evidence of viral integration by PCR. The overall penetrance of leukemia in primary mice with evidence of viral integration was greater than 95%. Transplantation of leukemic cells from primary mice to secondary recipients was able to recapitulate the disease with the same phenotype in a shorter period of time with a penetrance of 100%. Karyotypic analysis of leukemic blasts from primary and secondary mice was normal. Clonal analysis of retroviral integration showed that leukemias generated in primary mice were either monoclonal or oligoclonal (two dominating clones) while the majority of secondary mice had monoclonal disease. At the level of the immunoglobulin (IgH) rearrangements, the B-precursor leukemias were always polyclonal in primary mice, with the presence of the germline rearrangement in addition to other rearrangements. New clones appeared in secondary recipients, suggesting constant rearrangement of the IgH locus. These data also support that a more primitive cell type that had not yet rearranged its immunoglobulin genes was the target of the transforming event, ruling out the possibility that a mature B cell is the target of the transformation. To our knowledge, these results provide the first examples of in vivo models where human hematopietic stem/progenitor cells are transformed into leukemia, recapitulating the features of the human disease. Also, this represents the first reliable in vivo model of B-precursor ALL using MLL fusion genes and highlights species-specific differences in the mechanisms of neoplastic transformation of human and murine cells. The very high penetrance, short latency, normal karyotype and multiple clones that contribute to the disease collectively demonstrate that expression of MLL fusions is sufficient to induce human leukemias in vivo and support the notion that the MLL leukemias are the result of a single genetic hit.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 | 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".