Coactivation of STAT5 and ERK suppressed transformation in B-cell acute lymphoblastic leukemia.
Major Finding: Coactivation of STAT5 and ERK suppressed transformation in B-cell acute lymphoblastic leukemia.
Concept: STAT5- or ERK-activating genetic lesions were common but nearly mutually exclusive in this cancer.
Impact: Reactivating a suppressed oncogenic pathway may synergize with inhibition of the primary driver.
In B-cell acute lymphoblastic leukemia (B-ALL) and other cancers, transformation of normal cells into malignant cells generally requires the accumulation of multiple genetic aberrations. In an analysis of 1,148 B-ALL cases, Chan and colleagues found that STAT5- or ERK-activating genetic lesions were common, occurring in 31.4% or 33.6% of cases, respectively; however, only 3% of cases had concurrent STAT5 and ERK activation, a much lower percentage than expected by chance. Consistent with this, in B-ALL patient-derived xenografts, STAT5 phosphorylation and ERK phosphorylation were inversely related. Further, intermittent treatment of Philadelphia chromosome–positive B-ALL cells with the tyrosine kinase inhibitor ponatinib (which reduces STAT5 signaling) until the development of resistance resulted in a switch from dependence on STAT5 signaling to ERK signaling and sensitivity to the MEK1/2 inhibitor trametinib. Activating genetic lesions affecting STAT5 or ERK were correlated with pro-B-cell or pre-B-cell phenotypes, respectively, and the transition from a pro-B-cell to a pre-B-cell phenotype in mouse bone marrow was associated with activation of the master transcription factor BCL6 (normally upregulated by ERK and downregulated by STAT5) and suppression of the master transcription factor MYC (normally upregulated by STAT5 and downregulated by ERK). Further investigation showed that STAT5 and ERK played opposing roles in leukemogenesis; for example, activation of STAT5 or ERK alone increased colony formation and cell proliferation, but activation of both pathways suppressed colony formation and cell proliferation. Additionally, genetic ablation of the STAT5 pathway in ERK-driven B-ALL cells or the ERK pathway in STAT5-driven B-ALL cells increased colony formation in vitro and reduced the time to leukemia initiation in vivo. These results suggested that reactivation of a suppressed oncogenic pathway may synergize with inhibition of the primary oncogenic driver, an idea supported by in vitro and in vivo experiments. Together, this work provides a new perspective on the roles of oncogenes in B-ALL and implies that a new treatment paradigm based on exploiting these opposing functions may be worth investigating further.
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