Heterogeneity of Patient-Derived Acute Myeloid Leukemia Cells Subjected to SYK In Vitro Inhibition
Abstract
:1. Introduction
2. Results
2.1. Dose–Response Studies of AML Cell Proliferation after Exposure to SYK Inhibitors
2.2. SYK Inhibition Demonstrated the Antiproliferative Effect in a Larger AML Patient Cohort
2.3. Antiproliferative Effects of SYK Inhibition Varied between AML Patients
2.4. Antiproliferative Effects of Fostamatinib and TAK-659 Were Significantly Higher in FLT3 Mutated AML Patients
2.5. SYK Inhibitors Decreased AML Cell Viability and Induced Apoptosis
2.6. SYK Inhibition Resulted in Reduced Release of Cytokines
3. Discussion
4. Materials and Methods
4.1. Patients and Primary Human AML Cells
4.2. Reagents
4.3. AML Cell Proliferation Assay
4.4. Apoptosis Assay
4.5. Cytokine Release
4.6. Statistics and Bioinformatics
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Inhibitor, Concentration | Median Percent Proliferation Compared to Control (Range) |
---|---|
Fostamatinib, 1 µM Fostamatinib, 0.1 µM | 27% (2–96) 74% (14–116) |
Entospletinib, 10 µM Entospletinib, 1 µM | 36% (4–109) 65% (9–101) |
Cerdulatinib, 0.05 µM Cerdulatinib, 0.01 µM | 66% (10–126) 86% (18–105) |
TAK-659, 0.5 µM TAK-659, 0.05 µM | 19% (2–112) 56% (9–103) |
RO9021, 5 µM RO9021, 0.5 µM | 20% (3–88) 66% (8–103) |
Cytokine | Number of Patients with Detectable Release | Median Levels (pg/mL) | Variation Range (pg/mL) |
---|---|---|---|
Chemokines | |||
CCL 2 | 8 | 1478 | 35.1–10,521 |
CCL3 | 11 | 1745 | 75–17,933 |
CCL4 | 11 | 980 | 91–12,622 |
CCL5 | 10 | 106 | 6.0–675 |
CXCL1 | 7 | 1007 | 59–6965 |
CXCL5 | 10 | 1064 | 178–16,771 |
CXCL10 | 11 | 8.9 | 0.2–290 |
Interleukins | |||
IL-1 Ra | 11 | 2453 | 134–29,599 |
IL-8 | 12 | 11,266 | 164–111,476 |
IL-1β | 9 | 24.6 | 6.4–458 |
IL-6 | 9 | 55 | 8.9–956 |
Growth factors | |||
G-CSF | 8 | 28.1 | 5.6–141 |
HGF | 11 | 65 | 14–806 |
TNF-α | 13 | 11.6 | 1–495 |
Protease system | |||
Cystatin C | 12 | 5302 | 1379–13,223 |
Serpin-E1 | 10 | 370 | 37.2–12,243 |
MMP-1 | 11 | 139 | 19.5–519 |
MMP-2 | 10 | 2808 | 1079–8714 |
Patient Characteristics | Observations | |
---|---|---|
Demographic Data and Disease History | ||
Gender (number, percent) | Female/male | 31/37 (46/54) |
Age, years (median, range) | 62 (17–87) | |
Disease History (number, percent) | De novo | 51 (75) |
Secondary | 15 (22) | |
Relapse | 2 (3) | |
Hematology (mean, range) | ||
Hemoglobin, g/dL | 9.9 (6.3–15.4) | |
Platelets, ×109/L | 77 (5–258) | |
AML cell differentiation (number, percent) | ||
FAB | M0-1 | 13 (19) |
M2 | 13 (19) | |
M3 | 1 (2) | |
M4-5 | 38 (56) | |
CD34 | Unclassified Positive (≥30%) Negative (≤30%) Unknown | 3 (4) 37 (54) 27 (40) 4 (6) |
Cytogenetic and genetic abnormalities (number, percent) | ||
Cytogenetics * | Favorable | 9 (13) |
Intermediate | 15 (22) | |
Normal | 31 (46) | |
Adverse | 11 (16) | |
Unknown | 2 (3) | |
FLT3 | Wild type | 39 (57) |
ITD TKD | 24 (37) 1 (2) | |
Unknown | 4 (6) | |
NPM1 | Wild type | 44 (65) |
Insertion | 22 (32) | |
Unknown | 2 (3) |
Inhibitor | Molecular Weight | Pharmacological Properties | Company | Chemical Structure | Cas Number |
---|---|---|---|---|---|
Fostamatinib Disodium (R788) | 624.42 | Oral prodrug of the active compound R406. Competitive SYK/FLT3 inhibitor. Demonstrated in vitro antiproliferative effect in concentrations of 0.8–8.1 µM to DLBCL [23] and 41 nM to CLL [24]. | MedChemExpress (Monmouth Junction, NJ, USA) | C23H24FN6Na2O9P | 1025687-58-4 |
Entospletinib (GS-9973) | 411.46 | Orally bioavailable, selective SYK inhibitor. Induced antiproliferative and proapoptotic effects in vitro in pre-B-ALL and pro-B-ALL cell lines with concentrations of 0.001–20 µM [22]. | MedChemExpress (Monmouth Junction, NJ, USA) | C23H21N7O | 1229208-44-9 |
Cerdulatinib (PRT062070; PRT2070) | 482 | Orally active, multi-targeted tyrosine kinase inhibitor to JAK1/JAK2/JAK3/TYK2 and SYK. Induced apoptosis of CLL cells in vitro with concentrations of 0.3–1 µM [25], suppressed cell proliferation, and reduced cell viability in T-cell lines with a concentration of 10 µM [26]. | Selleckchem (Houston, TX, USA) | C20H27N7O3S | 1198300-79-6 |
TAK-659 | 380.85 | Orally bioavailable, selective SYK inhibitor. Selective against most other kinases, but potent toward SYK and FLT3. Induced in vitro apoptosis of CLL cells in concentrations of 0.1–10 µM [27]. | Selleckchem (Houston, TX, USA) | C17H21FN6HCl | 1952251-28-3 |
RO9021 | 355.44 | Potent SYK inhibitor. Suppresses BCR signaling and B-cell proliferation at 1 µM [28]. | Selleckchem (Houston, TX, USA) | C18H25N7O | 1446790-62-0 |
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Brattås, M.K.; Hemsing, A.L.; Rye, K.P.; Hatfield, K.J.; Reikvam, H. Heterogeneity of Patient-Derived Acute Myeloid Leukemia Cells Subjected to SYK In Vitro Inhibition. Int. J. Mol. Sci. 2022, 23, 14706. https://doi.org/10.3390/ijms232314706
Brattås MK, Hemsing AL, Rye KP, Hatfield KJ, Reikvam H. Heterogeneity of Patient-Derived Acute Myeloid Leukemia Cells Subjected to SYK In Vitro Inhibition. International Journal of Molecular Sciences. 2022; 23(23):14706. https://doi.org/10.3390/ijms232314706
Chicago/Turabian StyleBrattås, Marte Karen, Anette Lodvir Hemsing, Kristin Paulsen Rye, Kimberley Joanne Hatfield, and Håkon Reikvam. 2022. "Heterogeneity of Patient-Derived Acute Myeloid Leukemia Cells Subjected to SYK In Vitro Inhibition" International Journal of Molecular Sciences 23, no. 23: 14706. https://doi.org/10.3390/ijms232314706