Pharmacogenomic Profiling of Pediatric Acute Myeloid Leukemia to Identify Therapeutic Vulnerabilities and Inform Functional Precision Medicine

Overview

Journal Blood Cancer Discov

Specialties Hematology
Oncology

Date 2022 Aug 12

PMID 35960210

Authors

Han Wang

Kathy Yuen Yee Chan

Chi Keung Cheng

Margaret H L Ng

Po Yi Lee

Frankie Wai Tsoi Cheng

Grace Kee See Lam

Tin Wai Chow

Shau Yin Ha

Alan K S Chiang

Wing Hang Leung

Anskar Y H Leung

Chi Chiu Wang

Tao Zhang

Xiao-Bing Zhang

Chi Chiu So

Yuet Ping Yuen

Qiwei Sun

Chi Zhang

Yaqun Xu

John Tak Kit Cheung

Wing Hei Ng

Patrick Ming-Kuen Tang

Wei Kang

Ka-Fai To

Wayne Yuk Wai Lee

Raymond S M Wong

Ellen Ngar Yun Poon

Qi Zhao

Junbin Huang

Chun Chen

Patrick Man Pan Yuen

Chi-Kong Li

Alex Wing Kwan Leung

Kam Tong Leung

Affiliations

Soon will be listed here.

Abstract

Significance: We conducted integrated drug and genomic profiling of patient biopsies to build the functional genomic landscape of pediatric AML. Age-specific differences in drug response and new gene-drug interactions were identified. The feasibility of functional precision medicine-guided management of children with high-risk AML was successfully demonstrated in two evaluable clinical cases. This article is highlighted in the In This Issue feature, p. 476.

Citing Articles

CD9 shapes glucocorticoid sensitivity in pediatric B-cell precursor acute lymphoblastic leukemia.

Zhang C, Chan K, Ng W, Cheung J, Sun Q, Wang H Haematologica. 2024; 109(9):2833-2845.

PMID: 38572553 PMC: 11367191. DOI: 10.3324/haematol.2023.282952.

Deep genomic characterization highlights complexities and prognostic markers of pediatric acute myeloid leukemia.

Cheng C, Yung Y, Chan H, Leung K, Chan K, Leung A Commun Biol. 2023; 6(1):356.

PMID: 37002311 PMC: 10066286. DOI: 10.1038/s42003-023-04732-2.

Ex Vivo Drug Sensitivity Correlates with Clinical Response and Supports Personalized Therapy in Pediatric AML.

Strachan D, Gu C, Kita R, Anderson E, Richardson M, Yam G Cancers (Basel). 2022; 14(24).

PMID: 36551725 PMC: 9777060. DOI: 10.3390/cancers14246240.

Ailanthone Inhibits Cell Proliferation in Tongue Squamous Cell Carcinoma via PI3K/AKT Pathway.

Wang S, Cui Q, Chen X, Zhu X, Lin K, Zheng Q Evid Based Complement Alternat Med. 2022; 2022:3859489.

PMID: 36387351 PMC: 9643058. DOI: 10.1155/2022/3859489.

References

Pemovska T, Kontro M, Yadav B, Edgren H, Eldfors S, Szwajda A . Individualized systems medicine strategy to tailor treatments for patients with chemorefractory acute myeloid leukemia. Cancer Discov. 2013; 3(12):1416-29. DOI: 10.1158/2159-8290.CD-13-0350. View

Leung K, Zhang C, Chan K, Li K, Cheung J, Ng M . CD9 blockade suppresses disease progression of high-risk pediatric B-cell precursor acute lymphoblastic leukemia and enhances chemosensitivity. Leukemia. 2019; 34(3):709-720. DOI: 10.1038/s41375-019-0593-7. View

Liu T, Rao J, Hu W, Cui B, Cai J, Liu Y . Distinct genomic landscape of Chinese pediatric acute myeloid leukemia impacts clinical risk classification. Nat Commun. 2022; 13(1):1640. PMC: 8960760. DOI: 10.1038/s41467-022-29336-y. View

Zhao J, Agarwal S, Ahmad H, Amin K, Bewersdorf J, Zeidan A . A review of FLT3 inhibitors in acute myeloid leukemia. Blood Rev. 2021; 52:100905. PMC: 9846716. DOI: 10.1016/j.blre.2021.100905. View

Bisaillon R, Moison C, Thiollier C, Krosl J, Bordeleau M, Lehnertz B . Genetic characterization of ABT-199 sensitivity in human AML. Leukemia. 2019; 34(1):63-74. DOI: 10.1038/s41375-019-0485-x. View

Larsson P, Engqvist H, Biermann J, Ronnerman E, Forssell-Aronsson E, Kovacs A . Optimization of cell viability assays to improve replicability and reproducibility of cancer drug sensitivity screens. Sci Rep. 2020; 10(1):5798. PMC: 7118156. DOI: 10.1038/s41598-020-62848-5. View

Pesenti C, Navone S, Guarnaccia L, Terrasi A, Costanza J, Silipigni R . The Genetic Landscape of Human Glioblastoma and Matched Primary Cancer Stem Cells Reveals Intratumour Similarity and Intertumour Heterogeneity. Stem Cells Int. 2019; 2019:2617030. PMC: 6431486. DOI: 10.1155/2019/2617030. View

Yang C, Boyson C, Di Liberto M, Huang X, Hannah J, Dorn D . CDK4/6 Inhibitor PD 0332991 Sensitizes Acute Myeloid Leukemia to Cytarabine-Mediated Cytotoxicity. Cancer Res. 2015; 75(9):1838-45. PMC: 4417369. DOI: 10.1158/0008-5472.CAN-14-2486. View

Aung M, Mills M, Bittencourt-Silvestre J, Keeshan K . Insights into the molecular profiles of adult and paediatric acute myeloid leukaemia. Mol Oncol. 2021; 15(9):2253-2272. PMC: 8410545. DOI: 10.1002/1878-0261.12899. View

10.

Kurtz S, Eide C, Kaempf A, Khanna V, Savage S, Rofelty A . Molecularly targeted drug combinations demonstrate selective effectiveness for myeloid- and lymphoid-derived hematologic malignancies. Proc Natl Acad Sci U S A. 2017; 114(36):E7554-E7563. PMC: 5594650. DOI: 10.1073/pnas.1703094114. View

11.

Miller C, White B, Dees N, Griffith M, Welch J, Griffith O . SciClone: inferring clonal architecture and tracking the spatial and temporal patterns of tumor evolution. PLoS Comput Biol. 2014; 10(8):e1003665. PMC: 4125065. DOI: 10.1371/journal.pcbi.1003665. View

12.

Karol S, Alexander T, Budhraja A, Pounds S, Canavera K, Wang L . Venetoclax in combination with cytarabine with or without idarubicin in children with relapsed or refractory acute myeloid leukaemia: a phase 1, dose-escalation study. Lancet Oncol. 2020; 21(4):551-560. PMC: 7153631. DOI: 10.1016/S1470-2045(20)30060-7. View

13.

Xu C, Gu X, Padmanabhan R, Wu Z, Peng Q, Dicarlo J . smCounter2: an accurate low-frequency variant caller for targeted sequencing data with unique molecular identifiers. Bioinformatics. 2018; 35(8):1299-1309. PMC: 6477992. DOI: 10.1093/bioinformatics/bty790. View

14.

Malani D, Kumar A, Bruck O, Kontro M, Yadav B, Hellesoy M . Implementing a Functional Precision Medicine Tumor Board for Acute Myeloid Leukemia. Cancer Discov. 2021; 12(2):388-401. PMC: 9762335. DOI: 10.1158/2159-8290.CD-21-0410. View

15.

Chaudhury S, OConnor C, Canete A, Bittencourt-Silvestre J, Sarrou E, Prendergast A . Age-specific biological and molecular profiling distinguishes paediatric from adult acute myeloid leukaemias. Nat Commun. 2018; 9(1):5280. PMC: 6290074. DOI: 10.1038/s41467-018-07584-1. View

16.

McLaren W, Gil L, Hunt S, Riat H, Ritchie G, Thormann A . The Ensembl Variant Effect Predictor. Genome Biol. 2016; 17(1):122. PMC: 4893825. DOI: 10.1186/s13059-016-0974-4. View

17.

Tavor S, Shalit T, Chapal Ilani N, Moskovitz Y, Livnat N, Groner Y . Dasatinib response in acute myeloid leukemia is correlated with FLT3/ITD, PTPN11 mutations and a unique gene expression signature. Haematologica. 2020; 105(12):2795-2804. PMC: 7726833. DOI: 10.3324/haematol.2019.240705. View

18.

Chen C, Liu Y, Rappaport A, Kitzing T, Schultz N, Zhao Z . MLL3 is a haploinsufficient 7q tumor suppressor in acute myeloid leukemia. Cancer Cell. 2014; 25(5):652-65. PMC: 4206212. DOI: 10.1016/j.ccr.2014.03.016. View

19.

Mcneer N, Philip J, Geiger H, Ries R, Lavallee V, Walsh M . Genetic mechanisms of primary chemotherapy resistance in pediatric acute myeloid leukemia. Leukemia. 2019; 33(8):1934-1943. PMC: 6687545. DOI: 10.1038/s41375-019-0402-3. View

20.

Madan V, Koeffler H . Differentiation therapy of myeloid leukemia: four decades of development. Haematologica. 2020; 106(1):26-38. PMC: 7776344. DOI: 10.3324/haematol.2020.262121. View