Glucocorticoid-resistant B Cell Acute Lymphoblastic Leukemia Displays Receptor Tyrosine Kinase Activation

Overview

Journal NPJ Genom Med

Specialty Genetics

Date 2019 Apr 10

PMID 30962949

Citations 12

Authors

Rohit A Chougule

Kinjal Shah

Sausan A Moharram

Johan Vallon-Christersson

Julhash U Kazi

Affiliations

Soon will be listed here.

Abstract

The response of childhood acute lymphoblastic leukemia (ALL) to dexamethasone predicts the long-term remission outcome. To explore the mechanisms of dexamethasone resistance in B cell ALL (B-ALL), we generated dexamethasone-resistant clones by prolonged treatment with dexamethasone. Using RNA-sequencing and high-throughput screening, we found that dexamethasone-resistant cells are dependent on receptor tyrosine kinases. Further analysis with phosphokinase arrays showed that the type III receptor tyrosine kinase FLT3 is constitutively active in resistant cells. Targeted next-generation and Sanger sequencing identified an internal tandem duplication mutation and a point mutation (R845G) in FLT3 in dexamethasone-resistant cells, which were not present in the corresponding sensitive clones. Finally, we showed that resistant cells displayed sensitivity to second-generation FLT3 inhibitors both in vitro and in vivo. Collectively, our data suggest that long-term dexamethasone treatment selects cells with a distinct genetic background, in this case oncogenic FLT3, and therefore therapies targeting FLT3 might be useful for the treatment of relapsed B-ALL patients.

Citing Articles

Advancements in the impact of human microbiota and probiotics on leukemia.

Zhang Y, Zhao X, Zhang J, Zhang Y, Wei Y Front Microbiol. 2024; 15:1423838.

PMID: 39021626 PMC: 11251910. DOI: 10.3389/fmicb.2024.1423838.

Glucocorticoids paradoxically promote steroid resistance in B cell acute lymphoblastic leukemia through CXCR4/PLC signaling.

Abdoul-Azize S, Hami R, Riou G, Derambure C, Charbonnier C, Vannier J Nat Commun. 2024; 15(1):4557.

PMID: 38811530 PMC: 11136999. DOI: 10.1038/s41467-024-48818-9.

Fmoc-FF hydrogels and nanogels for improved and selective delivery of dexamethasone in leukemic cells and diagnostic applications.

Gallo E, Diaferia C, Smaldone G, Rosa E, Pecoraro G, Morelli G Sci Rep. 2024; 14(1):9940.

PMID: 38688930 PMC: 11061151. DOI: 10.1038/s41598-024-60145-z.

Characterisation of FLT3 alterations in childhood acute lymphoblastic leukaemia.

Gutierrez-Camino A, Richer C, Ouimet M, Fuchs C, Langlois S, Khater F Br J Cancer. 2023; 130(2):317-326.

PMID: 38049555 PMC: 10803556. DOI: 10.1038/s41416-023-02511-8.

Venetoclax-Resistant T-ALL Cells Display Distinct Cancer Stem Cell Signatures and Enrichment of Cytokine Signaling.

Shah K, Al Ashiri L, Nasimian A, Ahmed M, Kazi J Int J Mol Sci. 2023; 24(5).

PMID: 36902436 PMC: 10003524. DOI: 10.3390/ijms24055004.

References

Rozovskaia T, Feinstein E, Mor O, Foa R, Blechman J, Nakamura T . Upregulation of Meis1 and HoxA9 in acute lymphocytic leukemias with the t(4 : 11) abnormality. Oncogene. 2001; 20(7):874-8. DOI: 10.1038/sj.onc.1204174. View

Armstrong S, Staunton J, Silverman L, Pieters R, den Boer M, Minden M . MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nat Genet. 2001; 30(1):41-7. DOI: 10.1038/ng765. View

Inoue H, Takemura H, Kawai Y, Yoshida A, Ueda T, Miyashita T . Dexamethasone-resistant human Pre-B leukemia 697 cell line evolving elevation of intracellular glutathione level: an additional resistance mechanism. Jpn J Cancer Res. 2002; 93(5):582-90. PMC: 5927028. DOI: 10.1111/j.1349-7006.2002.tb01294.x. View

Ross M, Shurtleff S, Williams W, Patel D, Mahfouz R, Behm F . Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling. Cancer Cell. 2002; 1(2):133-43. DOI: 10.1016/s1535-6108(02)00032-6. View

Norman M, Hearing S . Glucocorticoid resistance - what is known?. Curr Opin Pharmacol. 2002; 2(6):723-9. DOI: 10.1016/s1471-4892(02)00232-1. View

Tissing W, Meijerink J, den Boer M, Pieters R . Molecular determinants of glucocorticoid sensitivity and resistance in acute lymphoblastic leukemia. Leukemia. 2003; 17(1):17-25. DOI: 10.1038/sj.leu.2402733. View

Armstrong S, Kung A, Mabon M, Silverman L, Stam R, den Boer M . Inhibition of FLT3 in MLL. Validation of a therapeutic target identified by gene expression based classification. Cancer Cell. 2003; 3(2):173-83. DOI: 10.1016/s1535-6108(03)00003-5. View

Smith K, Chanda S, Lingbeek M, Ross D, Botstein D, van Lohuizen M . Bmi-1 regulation of INK4A-ARF is a downstream requirement for transformation of hematopoietic progenitors by E2a-Pbx1. Mol Cell. 2003; 12(2):393-400. DOI: 10.1016/s1097-2765(03)00277-6. View

Armstrong S, Mabon M, Silverman L, Li A, Gribben J, Fox E . FLT3 mutations in childhood acute lymphoblastic leukemia. Blood. 2003; 103(9):3544-6. DOI: 10.1182/blood-2003-07-2441. View

10.

Bachmann P, Gorman R, Mackenzie K, Lutze-Mann L, Lock R . Dexamethasone resistance in B-cell precursor childhood acute lymphoblastic leukemia occurs downstream of ligand-induced nuclear translocation of the glucocorticoid receptor. Blood. 2004; 105(6):2519-26. DOI: 10.1182/blood-2004-05-2023. View

11.

Xia Z, Popovic R, Chen J, Theisler C, Stuart T, Santillan D . The MLL fusion gene, MLL-AF4, regulates cyclin-dependent kinase inhibitor CDKN1B (p27kip1) expression. Proc Natl Acad Sci U S A. 2005; 102(39):14028-33. PMC: 1236570. DOI: 10.1073/pnas.0506464102. View

12.

Faber J, Krivtsov A, Stubbs M, Wright R, Davis T, Heuvel-Eibrink M . HOXA9 is required for survival in human MLL-rearranged acute leukemias. Blood. 2008; 113(11):2375-85. PMC: 2656267. DOI: 10.1182/blood-2007-09-113597. View

13.

Real P, Tosello V, Palomero T, Castillo M, Hernando E, de Stanchina E . Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia. Nat Med. 2008; 15(1):50-8. PMC: 2692090. DOI: 10.1038/nm.1900. View

14.

Mullighan C, Zhang J, Kasper L, Lerach S, Payne-Turner D, Phillips L . CREBBP mutations in relapsed acute lymphoblastic leukaemia. Nature. 2011; 471(7337):235-9. PMC: 3076610. DOI: 10.1038/nature09727. View

15.

Biddie S, John S, Sabo P, Thurman R, Johnson T, Schiltz R . Transcription factor AP1 potentiates chromatin accessibility and glucocorticoid receptor binding. Mol Cell. 2011; 43(1):145-55. PMC: 3138120. DOI: 10.1016/j.molcel.2011.06.016. View

16.

Rao N, McCalman M, Moulos P, Francoijs K, Chatziioannou A, Kolisis F . Coactivation of GR and NFKB alters the repertoire of their binding sites and target genes. Genome Res. 2011; 21(9):1404-16. PMC: 3166826. DOI: 10.1101/gr.118042.110. View

17.

Ratman D, Vanden Berghe W, Dejager L, Libert C, Tavernier J, Beck I . How glucocorticoid receptors modulate the activity of other transcription factors: a scope beyond tethering. Mol Cell Endocrinol. 2012; 380(1-2):41-54. DOI: 10.1016/j.mce.2012.12.014. View

18.

Driessen E, Van Roon E, Spijkers-Hagelstein J, Schneider P, De Lorenzo P, Valsecchi M . Frequencies and prognostic impact of RAS mutations in MLL-rearranged acute lymphoblastic leukemia in infants. Haematologica. 2013; 98(6):937-44. PMC: 3669451. DOI: 10.3324/haematol.2012.067983. View

19.

Inaba H, Greaves M, Mullighan C . Acute lymphoblastic leukaemia. Lancet. 2013; 381(9881):1943-55. PMC: 3816716. DOI: 10.1016/S0140-6736(12)62187-4. View

20.

Brumatti G, Salmanidis M, Kok C, Bilardi R, Sandow J, Silke N . HoxA9 regulated Bcl-2 expression mediates survival of myeloid progenitors and the severity of HoxA9-dependent leukemia. Oncotarget. 2013; 4(11):1933-47. PMC: 3875760. DOI: 10.18632/oncotarget.1306. View