Page 48 - 2021_10-Haematologica-web

S. Hultmark et al.
tions or dysregulated expression of MYC as part of their tumor mechanism may also benefit, as seen in chronic myeloid leukemia.50
In summary, our work highlights the importance of working with primary human samples in mechanistic studies and drug screening. We also show the value of combinatorial treatment to develop novel mutation agnostic therapeutic approaches for AML. Finally, our finding that a combination of PKC activation and BET inhibition promotes increased differentiation in FLT3 wild-type AML provides strong support for further inves- tigation towards clinical use.
Disclosures
No conflicts of interest to disclose.
Contributions
SH, AB, EK and MM contributed to the conception and
design of the study; SH, AB, and LS contributed to the develop- ment of the methodology; SH, AB, PB, RS, FE and MM ana- lyzed and interpreted the data; SH, AB, LS, PB, CS, TF, CL, SL, GJ, FE and MM wrote and reviewed the manuscript; LS, PB, SP-T, CS, TF, RS, CL, SL and GJ provided technical or material support; AB, FE and MM supervised the study.
Acknowledgments
We thank the staff at the Lund Stem Cell FACS Core Facilities for assistance with cell sorting. We also thank Sofia Bengtsson for helping with primary samples and Ben Van Handel for proofreading the manuscript.
Funding
This work was supported by the Swedish Cancer Foundation, the Swedish Childhood Cancer Foundation, the Swedish Society for Medical Research, the Kamprad Foundation, Gunnar Nilsson and Crafoord.
References
1. Saultz JN, Garzon R. Acute myeloid leukemia: a concise review. J Clin Med. 2016;5(3):33.
2. Juliusson G, Lazarevic V, Horstedt AS, Hagberg O, Hoglund M, Swedish Acute Leukemia Registry Group. Acute myeloid leukemia in the real world: why population- based registries are needed. Blood. 2012;119 (17):3890-3899.
3. Pollyea DA, Tallman MS, de Botton S, et al. Enasidenib, an inhibitor of mutant IDH2 proteins, induces durable remissions in older patients with newly diagnosed acute myeloid leukemia. Leukemia. 2019;33(11): 2575-2584.
4. Waitkus MS, Diplas BH, Yan H. Biological role and therapeutic potential of IDH muta- tions in cancer. Cancer Cell. 2018;34(2):186- 195.
5.Kalmanti L, Saussele S, Lauseker M, et al. Safety and efficacy of imatinib in CML over a period of 10 years: data from the random- ized CML-study IV. Leukemia. 2015;29(5): 1123-1132.
6. Lo-Coco F, Di Donato L, GIMEMA; Schlenk RF, German-Austrian Acute Myeloid Leukemia Study Group and Study Alliance Leukemia. Targeted therapy alone for acute promyelocytic leukemia. N Engl J Med. 2016;374(12):1197-1198.
7. Daver N, Schlenk RF, Russell NH, Levis MJ. Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia. 2019;33(2):299-312.
8. Coombs CC, Tallman MS, Levine RL. Molecular therapy for acute myeloid leukaemia. Nat Rev Clin Oncol. 2016;13(5): 305-318.
9. Amatangelo MD, Quek L, Shih A, et al. Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response. Blood. 2017;130(6):732-741.
10. Cortes JE, Khaled S, Martinelli G, et al. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a mul- ticentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2019;20(7):984- 997.
11.Quek L, David MD, Kennedy A, et al. Clonal heterogeneity of acute myeloid leukemia treated with the IDH2 inhibitor enasidenib. Nat Med. 2018;24(8):1167-1177.
12. Kasi PM, Litzow MR, Patnaik MM, Hashmi
SK, Gangat N. Clonal evolution of AML on novel FMS-like tyrosine kinase-3 (FLT3) inhibitor therapy with evolving actionable targets. Leuk Res Rep. 2016;5:7-10.
13. Ablain J, Rice K, Soilihi H, de Reynies A, Minucci S, de The H. Activation of a promyelocytic leukemia-tumor protein 53 axis underlies acute promyelocytic leukemia cure. Nat Med. 2014;20(2):167-174.
14. de The H. Differentiation therapy revisited. Nat Rev Cancer. 2018;18(2):117-127.
15. Shen ZX, Shi ZZ, Fang J, et al. All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 2004;101 (15):5328-5335.
16. Cancer Genome Atlas Research N, Ley TJ, Miller C, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368(22):2059- 2074.
17. Baudet A, Ek F, Davidsson J, et al. Small mol- ecule screen identifies differentiation-pro- moting compounds targeting genetically diverse acute myeloid leukaemia. Br J Haematol. 2016;175(2):342-346.
18. Griessinger E, Anjos-Afonso F, Pizzitola I, et al. A niche-like culture system allowing the maintenance of primary human acute myeloid leukemia-initiating cells: a new tool to decipher their chemoresistance and self- renewal mechanisms. Stem Cells Transl Med. 2014;3(4):520-529.
19.Klco JM, Spencer DH, Miller CA, et al. Functional heterogeneity of genetically defined subclones in acute myeloid leukemia. Cancer Cell. 2014;25(3):379-392.
20. Zeidman R, Lofgren B, Pahlman S, Larsson C. PKCepsilon, via its regulatory domain and independently of its catalytic domain, induces neurite-like processes in neuroblas- toma cells. J Cell Biol. 1999;145(4):713-726.
21. Magnusson M, Sierra MI, Sasidharan R, et al. Expansion on stromal cells preserves the undifferentiated state of human hematopoi- etic stem cells despite compromised recon- stitution ability. PLoS One. 2013;8(1): e53912.
22. Salehi B, Iriti M, Vitalini S, et al. Euphorbia- derived natural products with potential for use in health maintenance. Biomolecules. 2019;9(8):337.
23. Fry DW, Harvey PJ, Keller PR, et al. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activ-
ity in human tumor xenografts. Mol Cancer
Ther. 2004;3(11):1427-1438.
24. Bagger FO, Kinalis S, Rapin N. BloodSpot: a
database of healthy and malignant haematopoiesis updated with purified and single cell mRNA sequencing profiles. Nucleic Acids Res. 2019;47(D1):D881-D885.
25. Lawrence T, Natoli G. Transcriptional regu- lation of macrophage polarization: enabling diversity with identity. Nat Rev Immunol. 2011;11(11):750-761.
26. Zhang H, Li L, Liu L. FcgammaRI (CD64) contributes to the severity of immune inflammation through regulating NF- kappaB/NLRP3 inflammasome pathway. Life Sci. 2018;207:296-303.
27. Zeke A, Misheva M, Remenyi A, Bogoyevitch MA. JNK signaling: regulation and functions based on complex protein- protein partnerships. Microbiol Mol Biol Rev. 2016;80(3):793-835.
28.Thangavelu K, Pan CQ, Karlberg T, et al. Structural basis for the allosteric inhibitory mechanism of human kidney-type glutami- nase (KGA) and its regulation by Raf-Mek- Erk signaling in cancer cell metabolism. Proc Natl Acad Sci U S A. 2012;109(20):7705- 7710.
29. Toullec D, Pianetti P, Coste H, et al. The bisindolylmaleimide GF 109203X is a potent and selective inhibitor of protein kinase C. J Biol Chem. 1991;266(24):15771-15781.
30. Mochly-Rosen D, Das K, Grimes KV. Protein kinase C, an elusive therapeutic tar- get? Nat Rev Drug Discov. 2012;11(12):937- 957.
31. Devaiah BN, Lewis BA, Cherman N, et al. BRD4 is an atypical kinase that phosphory- lates serine2 of the RNA polymerase II car- boxy-terminal domain. Proc Natl Acad Sci U S A. 2012;109(18):6927-6932.
32. Wong C, Laddha SV, Tang L, et al. The bro- modomain and extra-terminal inhibitor CPI203 enhances the antiproliferative effects of rapamycin on human neuroendocrine tumors. Cell Death Dis. 2014;5(10):e1450.
33. Bedoya LM, Marquez N, Martinez N, et al. SJ23B, a jatrophane diterpene activates clas- sical PKCs and displays strong activity against HIV in vitro. Biochem Pharmacol. 2009;77(6):965-978.
34. Hughes PJ, Marcinkowska E, Gocek E, Studzinski GP, Brown G. Vitamin D3-driven signals for myeloid cell differentiation-- implications for differentiation therapy. Leuk Res. 2010;34(5):553-565.
2576
haematologica | 2021; 106(10)