Transplantation of Immunodeficient Mice with Chronic Myeloid Leukemia (CML) Cells from Chronic Phase Patients Reveals a Hierarchy of CD34+ Aldehyde Dehydrogenase-Positive Cells with Short- and Long-Term Repopulating Activity and Transient Responsiveness to Imatinib Mesylate in Vivo.
Bibliographic record
Abstract
Abstract Transplantation of sublethally irradiated NOD/SCID or NOD/SCID-β2microglobulin (β2m) null mice with cells from most chronic phase chronic myeloid leukemia (CML) patients results in the regeneration in the mice of primarily normal human hematopoietic cells. This is due to the usual predominance of normal cells within the most primitive subsets of bone marrow or blood cells in these patients. To date, no markers that allow the most primitive normal and leukemic cells to be differentially isolated from chronic phase CML samples have been identified except those reflecting an increased turnover of the leukemic cells. As an alternative approach to characterizing chronic phase CML stem cells, we have identified particular patient samples that contain predominantly leukemic LTC-ICs and have found that transplants of these samples regenerate a predominance of leukemic cells in both NOD/SCID and NOD/SCID-β2m null mice. To investigate the biological and phenotypic properties of CML cells that have short- and longterm repopulating activity, we transplanted sublethally irradiated NOD/SCID and NOD/SCID-β2m null mice with FACS-sorted subsets of lin- CML cells from 2 such samples and then monitored their output of cells in the bone marrow of the mice for up to 12 weeks. The CD34+CD38+ CML cells produced a rapid but transient wave of mainly myeloid progeny that peaked at 3 weeks whereas the CD34+CD38− cells produced a more delayed but persistent wave of cells in both types of mice that included some lymphoid progeny although the latter represented a markedly reduced proportion of the total relative to the cells produced by normal human bone marrow. These patterns were seen in both recipient genotypes but cell output was enhanced in NOD/SCID-β2m null mice as expected for short-term repopulating cells. In additional studies with 3 patients’ samples, both types of repopulating cells were found primarily in the aldehyde dehydrogenase-positive fraction based on their staining with BODIPY-labeled amino acetaldehyde. To test the feasibility of the CML xenograft model for evaluating novel treatments in vivo, groups of NOD/SCID mice repopulated to high levels with leukemic cells (49±8%) 7 weeks after being transplanted with 3x107 CD34+ CML cells, were injected with 50 mg/kg imatinib mesylate (or not) i.p. twice daily for 10 days. Bone marrow samples obtained from the imatinib mesylate-treated mice 2, 4, 12 and 22 weeks after initiation of this treatment, initially showed a more rapid and greater decline of human leukemic cells (>2-fold as assessed by both FACS and quantitative real-time PCR); however by 5 months after completion of the treatment, the level of human cells in the bone marrow of both the imatinib mesylate-treated and untreated mice was the same. Taken together, these findings demonstrate that the CML clone in chronic phase patients contains a similar hierarchy of short and longterm repopulating cells as is found in normal adult bone marrow, and that the CML repopulating cells have, in addition to their ability to sustain the clone, a greater innate resistance to the toxic effects that imatinib mesylate has in vivo on the majority population of more differentiated CML cells.
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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) | 0.003 | 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".