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CRLF2 rearrangement in Ph-like acute lymphoblastic leukemia predicts relative glucocorticoid resistance that is overcome with MEK or Akt inhibition.
PLoS One 2019; 14(7):e0220026Plos

Abstract

Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL) is a genetically heterogeneous subtype of B-cell ALL characterized by chromosomal rearrangements and mutations that result in aberrant cytokine receptor and kinase signaling. In particular, chromosomal rearrangements resulting in the overexpression of cytokine receptor-like factor 2 (CRLF2) occur in 50% of Ph-like ALL cases. CRLF2 overexpression is associated with particularly poor clinical outcomes, though the molecular basis for this is currently unknown. Glucocorticoids (GCs) are integral to the treatment of ALL and GC resistance at diagnosis is an important negative prognostic factor. Given the importance of GCs in ALL therapy and the poor outcomes for patients with CRLF2 overexpression, we hypothesized that the aberrant signal transduction associated with CRLF2 overexpression might mediate intrinsic GC insensitivity. To test this hypothesis, we exposed Ph-like ALL cells from patient-derived xenografts to GCs and found that CRLF2 rearranged (CRLF2R) leukemias uniformly demonstrated reduced GC sensitivity in vitro. Furthermore, targeted inhibition of signal transduction with the MEK inhibitor trametinib and the Akt inhibitor MK2206, but not the JAK inhibitor ruxolitinib, was sufficient to augment GC sensitivity. These data suggest that suboptimal GC responses may in part underlie the poor clinical outcomes for patients with CRLF2 overexpression and provide rationale for combination therapy involving GCs and signal transduction inhibitors as a means of enhancing GC efficacy.

Authors+Show Affiliations

Department of Pediatrics, University of California, San Francisco, CA, United States of America.Department of Pediatrics, University of California, San Francisco, CA, United States of America.Department of Pediatrics, University of Pennsylvania, Philadelphia, PA, United States of America.Department of Pediatrics, University of California, San Francisco, CA, United States of America.Department of Pediatrics, University of Pennsylvania, Philadelphia, PA, United States of America.Department of Pediatrics, University of California, San Francisco, CA, United States of America.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31318944

Citation

Meyer, Lauren K., et al. "CRLF2 Rearrangement in Ph-like Acute Lymphoblastic Leukemia Predicts Relative Glucocorticoid Resistance That Is Overcome With MEK or Akt Inhibition." PloS One, vol. 14, no. 7, 2019, pp. e0220026.
Meyer LK, Delgado-Martin C, Maude SL, et al. CRLF2 rearrangement in Ph-like acute lymphoblastic leukemia predicts relative glucocorticoid resistance that is overcome with MEK or Akt inhibition. PLoS ONE. 2019;14(7):e0220026.
Meyer, L. K., Delgado-Martin, C., Maude, S. L., Shannon, K. M., Teachey, D. T., & Hermiston, M. L. (2019). CRLF2 rearrangement in Ph-like acute lymphoblastic leukemia predicts relative glucocorticoid resistance that is overcome with MEK or Akt inhibition. PloS One, 14(7), pp. e0220026. doi:10.1371/journal.pone.0220026.
Meyer LK, et al. CRLF2 Rearrangement in Ph-like Acute Lymphoblastic Leukemia Predicts Relative Glucocorticoid Resistance That Is Overcome With MEK or Akt Inhibition. PLoS ONE. 2019;14(7):e0220026. PubMed PMID: 31318944.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - CRLF2 rearrangement in Ph-like acute lymphoblastic leukemia predicts relative glucocorticoid resistance that is overcome with MEK or Akt inhibition. AU - Meyer,Lauren K, AU - Delgado-Martin,Cristina, AU - Maude,Shannon L, AU - Shannon,Kevin M, AU - Teachey,David T, AU - Hermiston,Michelle L, Y1 - 2019/07/18/ PY - 2019/04/18/received PY - 2019/07/08/accepted PY - 2019/7/19/entrez PY - 2019/7/19/pubmed PY - 2019/7/19/medline SP - e0220026 EP - e0220026 JF - PloS one JO - PLoS ONE VL - 14 IS - 7 N2 - Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL) is a genetically heterogeneous subtype of B-cell ALL characterized by chromosomal rearrangements and mutations that result in aberrant cytokine receptor and kinase signaling. In particular, chromosomal rearrangements resulting in the overexpression of cytokine receptor-like factor 2 (CRLF2) occur in 50% of Ph-like ALL cases. CRLF2 overexpression is associated with particularly poor clinical outcomes, though the molecular basis for this is currently unknown. Glucocorticoids (GCs) are integral to the treatment of ALL and GC resistance at diagnosis is an important negative prognostic factor. Given the importance of GCs in ALL therapy and the poor outcomes for patients with CRLF2 overexpression, we hypothesized that the aberrant signal transduction associated with CRLF2 overexpression might mediate intrinsic GC insensitivity. To test this hypothesis, we exposed Ph-like ALL cells from patient-derived xenografts to GCs and found that CRLF2 rearranged (CRLF2R) leukemias uniformly demonstrated reduced GC sensitivity in vitro. Furthermore, targeted inhibition of signal transduction with the MEK inhibitor trametinib and the Akt inhibitor MK2206, but not the JAK inhibitor ruxolitinib, was sufficient to augment GC sensitivity. These data suggest that suboptimal GC responses may in part underlie the poor clinical outcomes for patients with CRLF2 overexpression and provide rationale for combination therapy involving GCs and signal transduction inhibitors as a means of enhancing GC efficacy. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/31318944/CRLF2_rearrangement_in_Ph-like_acute_lymphoblastic_leukemia_predicts_relative_glucocorticoid_resistance_that_is_overcome_with_MEK_or_Akt_inhibition L2 - http://dx.plos.org/10.1371/journal.pone.0220026 DB - PRIME DP - Unbound Medicine ER -