Star Wars Against Leukemia: Attacking the Clones

Overview

Journal Leukemia

Specialties Hematology
Oncology

Date 2024 Sep 2

PMID 39223295

Authors

Monika M Toma

Tomasz Skorski

Affiliations

Soon will be listed here.

Abstract

Leukemia, although most likely starts as a monoclonal genetic/epigenetic anomaly, is a polyclonal disease at manifestation. This polyclonal nature results from ongoing evolutionary changes in the genome/epigenome of leukemia cells to promote their survival and proliferation advantages. We discuss here how genetic and/or epigenetic aberrations alter intracellular microenvironment in individual leukemia clones and how extracellular microenvironment selects the best fitted clones. This dynamic polyclonal composition of leukemia makes designing an effective therapy a challenging task especially because individual leukemia clones often display substantial differences in response to treatment. Here, we discuss novel therapeutic approach employing single cell multiomics to identify and eradicate all individual clones in a patient.

References

Koppensteiner R, Samartzis E, Noske A, von Teichman A, Dedes I, Gwerder M . Effect of MRE11 loss on PARP-inhibitor sensitivity in endometrial cancer in vitro. PLoS One. 2014; 9(6):e100041. PMC: 4057395. DOI: 10.1371/journal.pone.0100041. View

Wang J, Ding Q, Fujimori H, Motegi A, Miki Y, Masutani M . Loss of CtIP disturbs homologous recombination repair and sensitizes breast cancer cells to PARP inhibitors. Oncotarget. 2015; 7(7):7701-14. PMC: 4884948. DOI: 10.18632/oncotarget.6715. View

Black J, McGranahan N . Genetic and non-genetic clonal diversity in cancer evolution. Nat Rev Cancer. 2021; 21(6):379-392. DOI: 10.1038/s41568-021-00336-2. View

Maifrede S, Martinez E, Nieborowska-Skorska M, Di Marcantonio D, Hulse M, Le B . MLL-AF9 leukemias are sensitive to PARP1 inhibitors combined with cytotoxic drugs. Blood Adv. 2018; 1(19):1467-1472. PMC: 5728460. DOI: 10.1182/bloodadvances.2017006247. View

Condorelli R, Spring L, OShaughnessy J, Lacroix L, Bailleux C, Scott V . Polyclonal RB1 mutations and acquired resistance to CDK 4/6 inhibitors in patients with metastatic breast cancer. Ann Oncol. 2017; 29(3):640-645. DOI: 10.1093/annonc/mdx784. View

Liu P, Lin C, Liu L, Lu Z, Tu Z, Liu H . RAD54B mutations enhance the sensitivity of ovarian cancer cells to poly(ADP-ribose) polymerase (PARP) inhibitors. J Biol Chem. 2022; 298(9):102354. PMC: 9463535. DOI: 10.1016/j.jbc.2022.102354. View

Fong J, Pignata L, Goy P, Kawabata K, Chun-Wei Lee S, Koh C . Therapeutic Targeting of RNA Splicing Catalysis through Inhibition of Protein Arginine Methylation. Cancer Cell. 2019; 36(2):194-209.e9. PMC: 7194031. DOI: 10.1016/j.ccell.2019.07.003. View

Morita K, Wang F, Jahn K, Hu T, Tanaka T, Sasaki Y . Clonal evolution of acute myeloid leukemia revealed by high-throughput single-cell genomics. Nat Commun. 2020; 11(1):5327. PMC: 7577981. DOI: 10.1038/s41467-020-19119-8. View

Moldovan G, DAndrea A . How the fanconi anemia pathway guards the genome. Annu Rev Genet. 2009; 43:223-49. PMC: 2830711. DOI: 10.1146/annurev-genet-102108-134222. View

10.

Yun C, Mengwasser K, Toms A, Woo M, Greulich H, Wong K . The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci U S A. 2008; 105(6):2070-5. PMC: 2538882. DOI: 10.1073/pnas.0709662105. View

11.

Klimovich B, Merle N, Neumann M, Elmshauser S, Nist A, Mernberger M . p53 partial loss-of-function mutations sensitize to chemotherapy. Oncogene. 2021; 41(7):1011-1023. PMC: 8837531. DOI: 10.1038/s41388-021-02141-5. View

12.

Riley P . Epimutation and Cancer: Carcinogenesis Viewed as Error-Prone Inheritance of Epigenetic Information. J Oncol. 2018; 2018:2645095. PMC: 6008765. DOI: 10.1155/2018/2645095. View

13.

Zeller C, Dai W, Steele N, Siddiq A, Walley A, Wilhelm-Benartzi C . Candidate DNA methylation drivers of acquired cisplatin resistance in ovarian cancer identified by methylome and expression profiling. Oncogene. 2012; 31(42):4567-76. DOI: 10.1038/onc.2011.611. View

14.

McMahon C, Ferng T, Canaani J, Wang E, Morrissette J, Eastburn D . Clonal Selection with RAS Pathway Activation Mediates Secondary Clinical Resistance to Selective FLT3 Inhibition in Acute Myeloid Leukemia. Cancer Discov. 2019; 9(8):1050-1063. DOI: 10.1158/2159-8290.CD-18-1453. View

15.

Saito Y, Mochizuki Y, Ogahara I, Watanabe T, Hogdal L, Takagi S . Overcoming mutational complexity in acute myeloid leukemia by inhibition of critical pathways. Sci Transl Med. 2017; 9(413). PMC: 6377281. DOI: 10.1126/scitranslmed.aao1214. View

16.

Rerolle D, Wu H, de The H . Acute Promyelocytic Leukemia, Retinoic Acid, and Arsenic: A Tale of Dualities. Cold Spring Harb Perspect Med. 2024; 14(9). PMC: 11368190. DOI: 10.1101/cshperspect.a041582. View

17.

Tsujino T, Takai T, Hinohara K, Gui F, Tsutsumi T, Bai X . CRISPR screens reveal genetic determinants of PARP inhibitor sensitivity and resistance in prostate cancer. Nat Commun. 2023; 14(1):252. PMC: 9845315. DOI: 10.1038/s41467-023-35880-y. View

18.

Woerner J, Huang Y, Hutter S, Gurnari C, Hernandez Sanchez J, Wang J . Circulating microbial content in myeloid malignancy patients is associated with disease subtypes and patient outcomes. Nat Commun. 2022; 13(1):1038. PMC: 8873459. DOI: 10.1038/s41467-022-28678-x. View

19.

Tothova Z, Valton A, Gorelov R, Vallurupalli M, Krill-Burger J, Holmes A . Cohesin mutations alter DNA damage repair and chromatin structure and create therapeutic vulnerabilities in MDS/AML. JCI Insight. 2020; 6(3). PMC: 7934867. DOI: 10.1172/jci.insight.142149. View

20.

Boila L, Sengupta A . Unifying targeted therapy for leukemia in the era of PARP inhibition. Exp Hematol. 2023; 124:1-14. DOI: 10.1016/j.exphem.2023.05.005. View