CRLF2 rearrangement in Ph-like acute lymphoblastic leukemia predicts relative glucocorticoid resistance that is overcome with MEK or Akt inhibition.

Lauren K Meyer,Cristina Delgado-Martin,Kevin M Shannon,Shannon L Maude,David T Teachey,Michelle L Hermiston,Francesco Bertolini

doi:10.1371/journal.pone.0220026

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.

Highlights

Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL) is a subtype of B-cell ALL that displays a gene expression profile resembling that of BCR-ABL1-positive ALL but lacks the BCR-ABL1 translocation
We demonstrated that GC sensitivity could be significantly enhanced with concomitant signal transduction inhibition, providing rationale for further evaluation of a combination therapy strategy as a means of augmenting GC sensitivity in patients with cytokine receptor-like factor 2 (CRLF2) overexpression
CRLF2 rearrangement predicts steroid resistance these signal transduction inhibitors demonstrated variable effects, with some modulation of DEX sensitivity in several samples that demonstrated relative insensitivity to DEX as a single agent (S3B–S3D Fig). These data demonstrate that Ph-like ALL samples with CRLF2 rearrangements uniformly demonstrate limited GC sensitivity in vitro. These data suggest a model whereby dysregulated signal transduction in the context of CRLF2 overexpression contributes to relative GC resistance

Summary

Introduction

Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL) is a subtype of B-cell ALL that displays a gene expression profile resembling that of BCR-ABL1-positive ALL but lacks the BCR-ABL1 translocation. Ph-like ALL is characterized by genetic alterations that result in aberrant cytokine receptor and kinase signaling [1]. Foundationcenter.org/fdo-grantmaker-profile/?key= CAMP051), American Cancer Society Research Scholar Grant RSG-14-022-01-CDD (DTT; https:// www.cancer.org), and a St. Baldrick’s Scholar Award (SLM; https://www.stbaldricks.org). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

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