MAPK signaling cascades mediate distinct glucocorticoid resistance mechanisms in pediatric leukemia

Courtney L. Jones, Christy M. Gearheart, Susan Fosmire, Cristina Delgado-Martin, Nikki A. Evensen, Karen Bride, Angela J. Waanders, Faye Pais, Jinhua Wang, Teena Bhatla, Danielle S. Bitterman, Simone R. De Rijk, Wallace Bourgeois, Smita Dandekar, Eugene Park, Tamara M. Burleson, Pillai Pallavi Madhusoodhan, David T. Teachey, Elizabeth A. Raetz, Michelle L. HermistonMarkus Müschen, Mignon L. Loh, Stephen P. Hunger, Jinghui Zhang, Michael J. Garabedian, Christopher C. Porter, William L. Carroll

Research output: Contribution to journalArticle

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Abstract

The outcome for pediatric acute lymphoblastic leukemia (ALL) patients who relapse is dismal. A hallmark of relapsed disease is acquired resistance to multiple chemotherapeutic agents, particularly glucocorticoids. In this study, we performed a genome-scale short hairpin RNA screen to identify mediators of prednisolone sensitivity in ALL cell lines. The incorporation of these data with an integrated analysis of relapse-specific genetic and epigenetic changes allowed us to identify the mitogen-activated protein kinase (MAPK) pathway as a mediator of prednisolone resistance in pediatric ALL. We show that knock down of the specific MAPK pathway membersMEK2andMEK4increased sensitivity to prednisolone through distinct mechanisms. MEK4 knockdown increased sensitivity specifically to prednisolone by increasing the levels of the glucocorticoid receptor. MEK2 knockdown increased sensitivity to all chemotherapy agents tested by increasing the levels of p53. Furthermore, we demonstrate that inhibition of MEK1/2 with trametinib increased sensitivity of ALL cells and primary samples to chemotherapy in vitro and in vivo. To confirm a role for MAPK signaling in patients with relapsed ALL, we measured the activation of the MEK1/2 target ERK in matched diagnosis-relapse primary samples and observed increased phosphorylated ERK levels at relapse. Furthermore, relapse samples have an enhanced response to MEK inhibition compared to matched diagnosis samples in xenograft models. Together, our data indicate that inhibition of the MAPK pathway increases chemosensitivity to glucocorticoids and possibly other agents and that the MAPK pathway is an attractive target for prevention and/or treatment of relapsed disease.

Original languageEnglish (US)
Pages (from-to)2202-2212
Number of pages11
JournalBlood
Volume126
Issue number19
DOIs
StatePublished - Nov 5 2015

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Pediatrics
Mitogen-Activated Protein Kinases
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Glucocorticoids
Prednisolone
Leukemia
Recurrence
Chemotherapy
Drug Therapy
Mitogen-Activated Protein Kinase Kinases
Glucocorticoid Receptors
Heterografts
Epigenomics
Small Interfering RNA
Genes
Chemical activation
Cells
Glucocorticoid Receptor Deficiency
Genome
Cell Line

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Jones, C. L., Gearheart, C. M., Fosmire, S., Delgado-Martin, C., Evensen, N. A., Bride, K., ... Carroll, W. L. (2015). MAPK signaling cascades mediate distinct glucocorticoid resistance mechanisms in pediatric leukemia. Blood, 126(19), 2202-2212. https://doi.org/10.1182/blood-2015-04-639138
Jones, Courtney L. ; Gearheart, Christy M. ; Fosmire, Susan ; Delgado-Martin, Cristina ; Evensen, Nikki A. ; Bride, Karen ; Waanders, Angela J. ; Pais, Faye ; Wang, Jinhua ; Bhatla, Teena ; Bitterman, Danielle S. ; De Rijk, Simone R. ; Bourgeois, Wallace ; Dandekar, Smita ; Park, Eugene ; Burleson, Tamara M. ; Madhusoodhan, Pillai Pallavi ; Teachey, David T. ; Raetz, Elizabeth A. ; Hermiston, Michelle L. ; Müschen, Markus ; Loh, Mignon L. ; Hunger, Stephen P. ; Zhang, Jinghui ; Garabedian, Michael J. ; Porter, Christopher C. ; Carroll, William L. / MAPK signaling cascades mediate distinct glucocorticoid resistance mechanisms in pediatric leukemia. In: Blood. 2015 ; Vol. 126, No. 19. pp. 2202-2212.
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abstract = "The outcome for pediatric acute lymphoblastic leukemia (ALL) patients who relapse is dismal. A hallmark of relapsed disease is acquired resistance to multiple chemotherapeutic agents, particularly glucocorticoids. In this study, we performed a genome-scale short hairpin RNA screen to identify mediators of prednisolone sensitivity in ALL cell lines. The incorporation of these data with an integrated analysis of relapse-specific genetic and epigenetic changes allowed us to identify the mitogen-activated protein kinase (MAPK) pathway as a mediator of prednisolone resistance in pediatric ALL. We show that knock down of the specific MAPK pathway membersMEK2andMEK4increased sensitivity to prednisolone through distinct mechanisms. MEK4 knockdown increased sensitivity specifically to prednisolone by increasing the levels of the glucocorticoid receptor. MEK2 knockdown increased sensitivity to all chemotherapy agents tested by increasing the levels of p53. Furthermore, we demonstrate that inhibition of MEK1/2 with trametinib increased sensitivity of ALL cells and primary samples to chemotherapy in vitro and in vivo. To confirm a role for MAPK signaling in patients with relapsed ALL, we measured the activation of the MEK1/2 target ERK in matched diagnosis-relapse primary samples and observed increased phosphorylated ERK levels at relapse. Furthermore, relapse samples have an enhanced response to MEK inhibition compared to matched diagnosis samples in xenograft models. Together, our data indicate that inhibition of the MAPK pathway increases chemosensitivity to glucocorticoids and possibly other agents and that the MAPK pathway is an attractive target for prevention and/or treatment of relapsed disease.",
author = "Jones, {Courtney L.} and Gearheart, {Christy M.} and Susan Fosmire and Cristina Delgado-Martin and Evensen, {Nikki A.} and Karen Bride and Waanders, {Angela J.} and Faye Pais and Jinhua Wang and Teena Bhatla and Bitterman, {Danielle S.} and {De Rijk}, {Simone R.} and Wallace Bourgeois and Smita Dandekar and Eugene Park and Burleson, {Tamara M.} and Madhusoodhan, {Pillai Pallavi} and Teachey, {David T.} and Raetz, {Elizabeth A.} and Hermiston, {Michelle L.} and Markus M{\"u}schen and Loh, {Mignon L.} and Hunger, {Stephen P.} and Jinghui Zhang and Garabedian, {Michael J.} and Porter, {Christopher C.} and Carroll, {William L.}",
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Jones, CL, Gearheart, CM, Fosmire, S, Delgado-Martin, C, Evensen, NA, Bride, K, Waanders, AJ, Pais, F, Wang, J, Bhatla, T, Bitterman, DS, De Rijk, SR, Bourgeois, W, Dandekar, S, Park, E, Burleson, TM, Madhusoodhan, PP, Teachey, DT, Raetz, EA, Hermiston, ML, Müschen, M, Loh, ML, Hunger, SP, Zhang, J, Garabedian, MJ, Porter, CC & Carroll, WL 2015, 'MAPK signaling cascades mediate distinct glucocorticoid resistance mechanisms in pediatric leukemia', Blood, vol. 126, no. 19, pp. 2202-2212. https://doi.org/10.1182/blood-2015-04-639138

MAPK signaling cascades mediate distinct glucocorticoid resistance mechanisms in pediatric leukemia. / Jones, Courtney L.; Gearheart, Christy M.; Fosmire, Susan; Delgado-Martin, Cristina; Evensen, Nikki A.; Bride, Karen; Waanders, Angela J.; Pais, Faye; Wang, Jinhua; Bhatla, Teena; Bitterman, Danielle S.; De Rijk, Simone R.; Bourgeois, Wallace; Dandekar, Smita; Park, Eugene; Burleson, Tamara M.; Madhusoodhan, Pillai Pallavi; Teachey, David T.; Raetz, Elizabeth A.; Hermiston, Michelle L.; Müschen, Markus; Loh, Mignon L.; Hunger, Stephen P.; Zhang, Jinghui; Garabedian, Michael J.; Porter, Christopher C.; Carroll, William L.

In: Blood, Vol. 126, No. 19, 05.11.2015, p. 2202-2212.

Research output: Contribution to journalArticle

TY - JOUR

T1 - MAPK signaling cascades mediate distinct glucocorticoid resistance mechanisms in pediatric leukemia

AU - Jones, Courtney L.

AU - Gearheart, Christy M.

AU - Fosmire, Susan

AU - Delgado-Martin, Cristina

AU - Evensen, Nikki A.

AU - Bride, Karen

AU - Waanders, Angela J.

AU - Pais, Faye

AU - Wang, Jinhua

AU - Bhatla, Teena

AU - Bitterman, Danielle S.

AU - De Rijk, Simone R.

AU - Bourgeois, Wallace

AU - Dandekar, Smita

AU - Park, Eugene

AU - Burleson, Tamara M.

AU - Madhusoodhan, Pillai Pallavi

AU - Teachey, David T.

AU - Raetz, Elizabeth A.

AU - Hermiston, Michelle L.

AU - Müschen, Markus

AU - Loh, Mignon L.

AU - Hunger, Stephen P.

AU - Zhang, Jinghui

AU - Garabedian, Michael J.

AU - Porter, Christopher C.

AU - Carroll, William L.

PY - 2015/11/5

Y1 - 2015/11/5

N2 - The outcome for pediatric acute lymphoblastic leukemia (ALL) patients who relapse is dismal. A hallmark of relapsed disease is acquired resistance to multiple chemotherapeutic agents, particularly glucocorticoids. In this study, we performed a genome-scale short hairpin RNA screen to identify mediators of prednisolone sensitivity in ALL cell lines. The incorporation of these data with an integrated analysis of relapse-specific genetic and epigenetic changes allowed us to identify the mitogen-activated protein kinase (MAPK) pathway as a mediator of prednisolone resistance in pediatric ALL. We show that knock down of the specific MAPK pathway membersMEK2andMEK4increased sensitivity to prednisolone through distinct mechanisms. MEK4 knockdown increased sensitivity specifically to prednisolone by increasing the levels of the glucocorticoid receptor. MEK2 knockdown increased sensitivity to all chemotherapy agents tested by increasing the levels of p53. Furthermore, we demonstrate that inhibition of MEK1/2 with trametinib increased sensitivity of ALL cells and primary samples to chemotherapy in vitro and in vivo. To confirm a role for MAPK signaling in patients with relapsed ALL, we measured the activation of the MEK1/2 target ERK in matched diagnosis-relapse primary samples and observed increased phosphorylated ERK levels at relapse. Furthermore, relapse samples have an enhanced response to MEK inhibition compared to matched diagnosis samples in xenograft models. Together, our data indicate that inhibition of the MAPK pathway increases chemosensitivity to glucocorticoids and possibly other agents and that the MAPK pathway is an attractive target for prevention and/or treatment of relapsed disease.

AB - The outcome for pediatric acute lymphoblastic leukemia (ALL) patients who relapse is dismal. A hallmark of relapsed disease is acquired resistance to multiple chemotherapeutic agents, particularly glucocorticoids. In this study, we performed a genome-scale short hairpin RNA screen to identify mediators of prednisolone sensitivity in ALL cell lines. The incorporation of these data with an integrated analysis of relapse-specific genetic and epigenetic changes allowed us to identify the mitogen-activated protein kinase (MAPK) pathway as a mediator of prednisolone resistance in pediatric ALL. We show that knock down of the specific MAPK pathway membersMEK2andMEK4increased sensitivity to prednisolone through distinct mechanisms. MEK4 knockdown increased sensitivity specifically to prednisolone by increasing the levels of the glucocorticoid receptor. MEK2 knockdown increased sensitivity to all chemotherapy agents tested by increasing the levels of p53. Furthermore, we demonstrate that inhibition of MEK1/2 with trametinib increased sensitivity of ALL cells and primary samples to chemotherapy in vitro and in vivo. To confirm a role for MAPK signaling in patients with relapsed ALL, we measured the activation of the MEK1/2 target ERK in matched diagnosis-relapse primary samples and observed increased phosphorylated ERK levels at relapse. Furthermore, relapse samples have an enhanced response to MEK inhibition compared to matched diagnosis samples in xenograft models. Together, our data indicate that inhibition of the MAPK pathway increases chemosensitivity to glucocorticoids and possibly other agents and that the MAPK pathway is an attractive target for prevention and/or treatment of relapsed disease.

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Jones CL, Gearheart CM, Fosmire S, Delgado-Martin C, Evensen NA, Bride K et al. MAPK signaling cascades mediate distinct glucocorticoid resistance mechanisms in pediatric leukemia. Blood. 2015 Nov 5;126(19):2202-2212. https://doi.org/10.1182/blood-2015-04-639138