The First Fully Experimental In Vivo Model of Human Leukemogenesis: Human Hematopoietic Stem Cells Infected with MLL-ENL Induce Pro-B Acute Lymphoblastic Leukemia in NOD/SCID Mice.
Bibliographic record
Abstract
Abstract Identification of genes and translocations involved in human leukemia, as well as classification and clustering by gene arrays, have greatly evolved in the past years. However, the mechanisms of human leukemogenesis remain to be elucidated and the failure to develop an in vivo model where primary human hematopoietic cells are transformed into leukemic cells represents a significant limitation. Using a retrovirus encoding the oncogene MLL-ENL resulting from the t(11;19)(q23;p13.3) translocation found in acute myeloid leukemias (AML) as well as in acute lymphoblastic leukemias (ALL) of B or T cell origin, we infected lineage-negative cord blood cells and injected those cells into sub-lethally irradiated NOD/SCID mice. 15 to 20 weeks after injection, all the mice developed an aggressive pro-B acute lymphoblastic leukemia characterized by immature B cells (CD10+, CD19+, CD20−, IgD−, IgM−) involving more than 90% of bone marrow. Spleen and thymus were increased in size and infiltrated with >90% leukemic cells. Furthermore, analysis of the lungs and liver showed significant infiltration of these organs. Transplantation of leukemic cells from primary mice to secondary recipients was able to recapitulate the disease with the same phenotype and the same organ involvement in a shorter period of time. If MLL-ENL transduced cells are grown in suspension culture with IL-3 and SCF, there is massive proliferation of cells blocked in differentiation along the monocytic lineage. In contrast to untransduced cells, colony-forming progenitors were maintained long term in these cultures and could be serially replated, suggestive of an enhanced capacity for self-renewal. After 50 to 70 days in culture, these cells were injected in NOD/SCID mice and mice were analyzed after 12 to 15 weeks. Monoblastic cells were engrafted in the bone marrow and spleen with the same phenotype of the cultured cells (CD33+, CD11b+, CD15+, HLA DR+). These cells were able to engraft secondary and tertiary recipients formally demostrating increased self-renewal capacity of the transformed stem cell. In a limited number of primary mice, transplanted with high cell doses, AML developed at 15 weeks post-transplant. To our knowledge, these results provide the first in vivo model where human hematopietic stem/progenitor cells are transformed into leukemia. Remarkably, depending on the cellular environment, MLL-ENL can induce ALL or AML in primary cells as a sole genetic event, although we cannot rule out the spontaneous acquistion of additional co-operating genetic or epigenetic abnormalities. This model provides a significant step forward to understand the mechanisms involved in human leukemogenesis.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.004 | 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".