Integrin Linked Kinase Is Expressed in Acute Myeloid Leukemia Blasts and Its Inhibition Is Cytotoxic to Leukemic Progenitors.
Bibliographic record
Abstract
Abstract Constitutive activation of the phosphatidylinositol-3-kinase (PI-3K) pathway is frequent in acute myeloid leukemia (AML) blasts and down-regulation of this pathway results in apoptotic death of these cells from many patient samples. Integrin linked kinase (ILK) is stimulated by activated PI-3K and ILK, in turn, activates AKT, a key downstream effector of the PI-3K pathway. The expression and activity of ILK are increased in a range of solid tumors. Small-molecule inhibitors of ILK activity have been identified and shown to inhibit tumour growth, invasion and angiogenesis. We investigated the possible role of ILK in AML blast and colony forming cell (AML-CFC) survival. Using Western blotting, ILK protein was detected in 30 of 35 primary AML blast samples although the levels seen were variable. ILK kinase activity correlated strongly with ILK protein expression as quantitated by densitometry (r = 0.91) in 6 samples where both were studied. Activation of the PI-3K pathway, as measured by detection of AKT phosphorylation on serine 473 (ser473), was also found in 27 of 30 samples expressing ILK protein. QLT0267 is a potent second generation small molecule inhibitor (from QLT Inc., Vancouver, Canada) which selectively inhibits the kinase activity of ILK but not a variety of other kinases. Treatment of AML blasts with QLT0267 resulted in a time and dose dependent decrease in p-AKT ser473 expression as well as downstream targets of AKT (p-S6, p-GSK-3β). 27 AML and 5 normal bone marrow (NBM) samples were incubated for 48h with QLT0267 or 10 μM of the PI-3K inhibitor, LY294002, and then plated in CFC assay. There was a direct correlation between the % AML-CFC kill seen with LY204002 and QLT0267 (r= 0.70 and 0.60 comparing % kill with LY294002 and QLT0267 at 3 and 10 μM, respectively). The IC50 of QLT0267 was ≤ 3μM for 6 of 23 AML samples and 0 of 5 NBM samples (range % kill of AML and normal CFC after treatment with 3μM; 0 – 86% and 0 – 23%, respectively). The IC90 for this inhibitor was ≤ 10μM for 9 of 27 AML and 0 of 5 NBMs (range % kill 6 – 99 and 30 – 68, respectively, for AML and normal CFC treated with 10μM QLT0267). Interestingly, AML-CFC from 4 AML samples in which ILK protein could not be detected were resistant to killing with QLT0267. Thus, ILK is expressed in a large proportion of AML samples. Inhibition of ILK kinase is cytotoxic to leukemic progenitors suggesting that this molecule is important for the survival of these cells. Approximately one third of AML samples tested were more susceptible to killing by ILK inhibition than NBM cells suggesting that selective targeting of malignant rather than normal hematopoietic cells may be achieved in some cases. Furthermore, it may be possible to predict which AML samples will be sensitive to inhibitors such as QLT0267 by measuring expression of the target protein.
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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".