CD47-Sirpα Interaction Modulates Homing and Engraftment of Human Acute Myeloid Leukemia Stem Cells in Mice.
Bibliographic record
Abstract
Abstract Abstract 476 Introduction: A large body of work has shown that acute myeloid leukemia (AML) clones are hierarchically organized and maintained by leukemia initiating cells (AML-LSC). However, little is known about molecular regulators that govern AML-LSC fate. Using the non-obese diabetic (NOD)–severe combined immunodeficiency (SCID) xenotransplantation model, our group recently found that CD47-SIRPα protein interaction is essential for repopulation of normal hematopoietic stem cells (HSC) in mice (Takenaka et al, Nat Immunol 2007). The NOD background conferred the best support for human engraftment, whereas mice with other polymorphisms of Sirpa could not be engrafted (i.e. NOD.NOR-Idd13.SCID). CD47 on human AML contributes to pathogenesis by inhibiting phagocytosis of leukemia cells through CD47-SIRPα interaction (Jaiswal et al, Cell 2009). CD47 is increased on human AML LSCs compared to normal HSCs, and high levels of CD47 are associated with poor patient outcome (Majeti et al, Cell 2009). This indicates that CD47 may function as an important molecular regulator of AML-LSC fate through communication with SIRPα protein expressed on cells of the innate immune system. Results: Consistent with published results, we observed increased CD47 expression in primary AML cells compared to normal cord blood cells. We next investigated the functional relevance of CD47 for AML-LSCs by xenografting primary human AMLs into NOD.SCID and NOD.NOR-Idd13.SCID (Idd) mice. Following intravenous (i.v.) transplantation, none of three primary human AML samples could engraft Idd mice while robust engraftment in NOD.SCID mice was observed, consistent with our previous data using normal human HSCs. When the same samples were transplanted intrafemorally (i.f.), 2 of 6 Idd mice showed engraftment in the injected femur but no engraftment in other bones or the spleen; evidence of the latter is linked to stem cell function. To assess the role of innate immunity, we pre-treated mice with antibody against murine CD122 which depletes host natural killer (NK) cells and macrophages. Engraftment in the injected femur was observed in NOD.SCID mice (43/43) for all 10 AML samples tested, and interestingly in 31 of 42 Idd mice (8/10 AML samples tested), with similar engraftment levels (Idd 37.4±6% vs NOD.SCID 53.8±5%, p=0.33). As expected, NOD.SCID mice supported migration to non-injected bones (38/43 mice, 10/10 AML samples tested). In contrast to results obtained in the absence of anti-CD122 pre-treatment, engraftment in non-injected bones was now detectable in 8 of 42 Idd mice (2/10 AML samples tested), pointing to improved migration of AML-LSCs following depletion of NK cells and macrophages. However, the engraftment level in non-injected bones was significantly lower in Idd compared to NOD.SCID mice (2.4±4% vs 63.2±6%, p=0.001). Moreover, AML-LSCs were unable to repopulate the spleens of Idd mice. Homing assays revealed decreased homing to BM and spleen 16 hours following i.v. injection in Idd compared to NOD.SCID mice. Conclusion: Our results support the hypothesis that CD47-SIRPα interaction is critical for engraftment of AML-LSCs. Attenuation of CD47-SIRPα interaction (as in Idd mice) leads to decreased engraftment ability of AML-LSCs. Enhancement of engraftment in the injected femur and in some cases migration to other bones in Idd mice following anti-CD122 treatment is likely mediated through interference with cells of the innate immune system. Interruption of CD47-SIRPα signaling through targeting of either CD47 or SIRPα provides a potential therapeutic approach for eradication of AML-LSCs. Disclosures: Dick: Roche: Research Funding; CSL Ltd: Research Funding.
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 | 0.000 | 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 | 0.001 |
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".