Activated JAK2 Signaling in Primary Human Hematopoietic Cells Drives Erythropoietin-Independent Erythropoiesis and Myelofibrosis.
Bibliographic record
Abstract
Abstract An activating mutation in the JAK2 tyrosine kinase has recently been identified in patients with polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF). However, at this time, evidence of a causative role for activated JAK2 signaling in the pathogenesis of these myeloproliferative disorders is limited. Given that these are clonal stem cell diseases, the impact of deregulated JAK-STAT signaling must be considered in the context of primitive human hematopoietic cells. To this end, a lentiviral vector encoding the TEL-JAK2 (5–19) fusion was employed to infect lineage-depleted human cord blood, resulting in constitutive activation of STAT5 as well as the ERK and PI-3 kinase signaling pathways. Interestingly, when grown in culture under conditions that normally support the exclusive production of cells from the granulopoietic and monocytic lineages, cells expressing TEL-JAK2 underwent a burst of erythropoietin (EPO)-independent erythropoiesis; an outcome that could even occur in serum-free media in the absence of supportive cytokines. Furthermore, TEL-JAK2 cells exhibited erythroid colony-forming capacity in the absence of exogeneous EPO, a hallmark of PV. In order to gain insight into the in vivo effects of activated JAK2 signaling, transduced cord blood cells were injected intrafemorally into sublethally irradiated NOD/SCID mice. When animals were sacrificed 3 weeks post-transplant, the percentage of human engraftment was comparable between TEL-JAK2 and control animals; however, total cellularity was significantly reduced in the injected femur of TEL-JAK2 mice. At 9 weeks post-transplant, this reduction in cellularity was noted not only in the injected femur, but also in distant marrow cavities. Histological examination of the bone marrow from TEL-JAK2-transplanted mice showed a decrease in cellularity, the presence of an atypical megakaryocyte population, and patent sinusoids. Most notably, reticulin staining revealed the existence of a fibrous network in the bone marrow of TEL-JAK2 mice, indicative of myelofibrotic change. Taken together, these in vitro and in vivo studies provide functional evidence that in human hematopoietic cells, activated JAK2 signaling can initiate disease processes bearing similarity to both PV and IMF. Furthermore, they provide the first example of an experimental xenotransplant model of IMF which can be utilized to provide insight into both the pathogenesis of this disease and potential therapeutic targets.
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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) | 0.002 | 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".