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

• Published in: PloS one 2019-07, Vol.14 (7), p.e0220026-e0220026
• Main Authors: Meyer, Lauren K, Delgado-Martin, Cristina, Maude, Shannon L, Shannon, Kevin M, Teachey, David T, Hermiston, Michelle L
• Format: Article
• Language: English
• Subjects: Acute lymphoblastic leukemia; Acute lymphocytic leukemia; AKT protein; Apoptosis; Biology and Life Sciences; Cell Line, Tumor; Cellular signal transduction; Chromosome rearrangements; Chromosomes; Complications and side effects; Cytokines; Dosage and administration; Drug Resistance, Neoplasm - genetics; Drug therapy; Gene expression; Gene Expression Regulation, Leukemic; Gene Rearrangement; Genetic aspects; Glucocorticoids; Glucocorticoids - pharmacology; Glucocorticoids - therapeutic use; Humans; Inhibition; Inhibitors; Kinases; Leukemia; Ligands; Lymphatic leukemia; Lymphocytes B; Lymphocytic leukemia; MAP Kinase Kinase Kinases - antagonists & inhibitors; Medical prognosis; Medicine and Health Sciences; MEK inhibitors; Mutation; Patients; Pediatrics; Philadelphia Chromosome; Physiological aspects; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Receptors, Cytokine - genetics; Research and Analysis Methods; Ruxolitinib; Sensitivity; Signal transduction; Signal Transduction - drug effects; Therapy; Xenografts; Xenotransplantation
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0220026

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.