Trib2 Expression in Granulocyte-monocyte Progenitors Drives a Highly Drug Resistant Acute Myeloid Leukaemia Linked to Elevated Bcl2

Overview

Journal Oncotarget

Specialty Oncology

Date 2018 Mar 31

PMID 29599919

Citations 9

Authors

Caitriona OConnor

Krishna Yalla

Mara Salome

Hothri Ananyambica Moka

Eduardo Gomez Castaneda

Patrick A Eyers

Karen Keeshan

Affiliations

Soon will be listed here.

Abstract

Trib2 pseudokinase has oncogenic and tumour suppressive functions depending on the cellular context. We investigated the ability of Trib2 to transform different haemopoietic stem and progenitor cells (HSPCs). Our study identified the granulocyte-macrophage progenitor (GMP) subpopulation as a potent leukaemia initiating cell of Trib2-driven AML . Trib2 transformed GMPs generated a fully penetrant and short latency AML. AML cells expressing elevated Trib2 led to a chemoresistant phenotype following chemotherapy treatment. We show that Trib2 overexpression results in an increase in BCL2 expression, and high Trib2 expressing cells are highly sensitive to cell killing by BCL2 inhibition (ABT199). Combined treatment with chemotherapeutic agents and BCL2 inhibition resulted in synergistic killing of Trib2+ AML cells. Trib2 transformed GMP AML cells showed more chemoresistance compared with HSPC derived Trib2 AML cells associated with higher expression. There is significant correlation of high and expression in patient derived human AML cells. These data demonstrate that the cell of origin influences the leukaemic profile and chemotherapeutic response of Trib2+ AML. Combined TRIB2 and BCL2 expression in AML cells may have clinical utility relevant for monitoring drug resistance and disease relapse.

Citing Articles

The role of tribbles homolog 2 in cell proliferation.

Zhang W, Li M, Zhang M, Yan G, Tang C Cell Commun Signal. 2025; 23(1):5.

PMID: 39762856 PMC: 11702054. DOI: 10.1186/s12964-024-01985-0.

Tribbles Pseudokinases in Colorectal Cancer.

Ferreira B, Santos B, Link W, De Sousa-Coelho A Cancers (Basel). 2021; 13(11).

PMID: 34198908 PMC: 8201230. DOI: 10.3390/cancers13112825.

The Critical Role of TRIB2 in Cancer and Therapy Resistance.

Mayoral-Varo V, Jimenez L, Link W Cancers (Basel). 2021; 13(11).

PMID: 34070799 PMC: 8198994. DOI: 10.3390/cancers13112701.

Tribbles homolog 2 (Trib2), a pseudo serine/threonine kinase in tumorigenesis and stem cell fate decisions.

Fang Y, Zekiy A, Ghaedrahmati F, Timoshin A, Farzaneh M, Anbiyaiee A Cell Commun Signal. 2021; 19(1):41.

PMID: 33794905 PMC: 8015142. DOI: 10.1186/s12964-021-00725-y.

Harmine and Piperlongumine Revert TRIB2-Mediated Drug Resistance.

Machado S, Silva A, De Sousa-Coelho A, Duarte I, Grenho I, Santos B Cancers (Basel). 2020; 12(12).

PMID: 33316942 PMC: 7763856. DOI: 10.3390/cancers12123689.

References

Jin G, Yamazaki Y, Takuwa M, Takahara T, Kaneko K, Kuwata T . Trib1 and Evi1 cooperate with Hoxa and Meis1 in myeloid leukemogenesis. Blood. 2007; 109(9):3998-4005. DOI: 10.1182/blood-2006-08-041202. View

Eyers P, Keeshan K, Kannan N . Tribbles in the 21st Century: The Evolving Roles of Tribbles Pseudokinases in Biology and Disease. Trends Cell Biol. 2016; 27(4):284-298. PMC: 5382568. DOI: 10.1016/j.tcb.2016.11.002. View

Li K, Wang F, Cao W, Lv X, Hua F, Cui B . TRIB3 Promotes APL Progression through Stabilization of the Oncoprotein PML-RARα and Inhibition of p53-Mediated Senescence. Cancer Cell. 2017; 31(5):697-710.e7. DOI: 10.1016/j.ccell.2017.04.006. View

Krivtsov A, Twomey D, Feng Z, Stubbs M, Wang Y, Faber J . Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature. 2006; 442(7104):818-22. DOI: 10.1038/nature04980. View

Paz-Priel I, Cai D, Wang D, Kowalski J, Blackford A, Liu H . CCAAT/enhancer binding protein alpha (C/EBPalpha) and C/EBPalpha myeloid oncoproteins induce bcl-2 via interaction of their basic regions with nuclear factor-kappaB p50. Mol Cancer Res. 2005; 3(10):585-96. DOI: 10.1158/1541-7786.MCR-05-0111. View

Rishi L, Hannon M, Salome M, Hasemann M, Frank A, Campos J . Regulation of Trib2 by an E2F1-C/EBPα feedback loop in AML cell proliferation. Blood. 2014; 123(15):2389-400. DOI: 10.1182/blood-2013-07-511683. View

Liang K, Paredes R, Carmody R, Eyers P, Meyer S, McCarthy T . Human TRIB2 Oscillates during the Cell Cycle and Promotes Ubiquitination and Degradation of CDC25C. Int J Mol Sci. 2016; 17(9). PMC: 5037658. DOI: 10.3390/ijms17091378. View

Huntly B, Shigematsu H, Deguchi K, Lee B, Mizuno S, Duclos N . MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors. Cancer Cell. 2004; 6(6):587-96. DOI: 10.1016/j.ccr.2004.10.015. View

Reckzeh K, Bereshchenko O, Mead A, Rehn M, Kharazi S, Jacobsen S . Molecular and cellular effects of oncogene cooperation in a genetically accurate AML mouse model. Leukemia. 2012; 26(7):1527-36. DOI: 10.1038/leu.2012.37. View

10.

Haferlach T, Kohlmann A, Wieczorek L, Basso G, Te Kronnie G, Bene M . Clinical utility of microarray-based gene expression profiling in the diagnosis and subclassification of leukemia: report from the International Microarray Innovations in Leukemia Study Group. J Clin Oncol. 2010; 28(15):2529-37. PMC: 5569671. DOI: 10.1200/JCO.2009.23.4732. View

11.

Storlazzi C, Fioretos T, Surace C, Lonoce A, Mastrorilli A, Strombeck B . MYC-containing double minutes in hematologic malignancies: evidence in favor of the episome model and exclusion of MYC as the target gene. Hum Mol Genet. 2006; 15(6):933-42. DOI: 10.1093/hmg/ddl010. View

12.

Tan S, Yam A, Lawton L, Wong R, Young R, Look A . TRIB2 reinforces the oncogenic transcriptional program controlled by the TAL1 complex in T-cell acute lymphoblastic leukemia. Leukemia. 2015; 30(4):959-62. PMC: 4724340. DOI: 10.1038/leu.2015.195. View

13.

Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Minden M . A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994; 367(6464):645-8. DOI: 10.1038/367645a0. View

14.

Liang K, Rishi L, Keeshan K . Tribbles in acute leukemia. Blood. 2013; 121(21):4265-70. DOI: 10.1182/blood-2012-12-471300. View

15.

Wouters B, Alberich Jorda M, Keeshan K, Louwers I, Erpelinck-Verschueren C, Tielemans D . Distinct gene expression profiles of acute myeloid/T-lymphoid leukemia with silenced CEBPA and mutations in NOTCH1. Blood. 2007; 110(10):3706-14. PMC: 2077318. DOI: 10.1182/blood-2007-02-073486. View

16.

Yokoyama T, Toki T, Aoki Y, Kanezaki R, Park M, Kanno Y . Identification of TRIB1 R107L gain-of-function mutation in human acute megakaryocytic leukemia. Blood. 2012; 119(11):2608-11. DOI: 10.1182/blood-2010-12-324806. View

17.

Eppert K, Takenaka K, Lechman E, Waldron L, Nilsson B, van Galen P . Stem cell gene expression programs influence clinical outcome in human leukemia. Nat Med. 2011; 17(9):1086-93. DOI: 10.1038/nm.2415. View

18.

Ye M, Zhang H, Yang H, Koche R, Staber P, Cusan M . Hematopoietic Differentiation Is Required for Initiation of Acute Myeloid Leukemia. Cell Stem Cell. 2015; 17(5):611-23. PMC: 4636971. DOI: 10.1016/j.stem.2015.08.011. View

19.

Lavau C, Szilvassy S, Slany R, Cleary M . Immortalization and leukemic transformation of a myelomonocytic precursor by retrovirally transduced HRX-ENL. EMBO J. 1997; 16(14):4226-37. PMC: 1170048. DOI: 10.1093/emboj/16.14.4226. View

20.

Bereshchenko O, Mancini E, Moore S, Bilbao D, Mansson R, Luc S . Hematopoietic stem cell expansion precedes the generation of committed myeloid leukemia-initiating cells in C/EBPalpha mutant AML. Cancer Cell. 2009; 16(5):390-400. DOI: 10.1016/j.ccr.2009.09.036. View