Combination of p-STAT5, CRLF2 and copy number alterations as a potential indicator of a high-risk subgroup of acute lymphoblastic leukemia.
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PURPOSE: Signal transduction and transcription activation5 (STAT5) drives leukemic cell survival and treatment resistance in acute lymphoblastic leukemia (ALL), linking its activation to poor prognosis and highlighting it as an important biomarker and therapeutic target. We hypothesized that integrating STAT activation, cytokine receptor-like factor2 (CRLF2) overexpression, and copy number alterations (CNAs) affecting B-cell differentiation, cell-cycle control, and proliferation could define a high-risk ALL subtype, possibly including Philadelphia (Ph) like ALL. METHODS: The study included 115 precursor-B-ALL patients, comprising 88 (76.5%) children and 27 (23.5%) adults, 66 males (57.4%) and 49 females (42.6%). Expressions of p-STAT3, p-STAT5, and CRLF2 were assessed by flow cytometry. Forty patients, including 29 with positive marker expression, of whom 18 lacked any of the recurrent genetic translocations, were further tested for CNAs by Multiplex Ligation-dependent Probe Amplification (MLPA). RESULTS: p-STAT3, p-STAT5, and/or CRLF2 were expressed in 36 (31.3%) patients. p-STAT3 was positive in 6 (5.2%) patients, p-STAT5 in 27 (23.4%) patients, and CRLF2 overexpression was detected in 15 (13.04%) patients. Thirty/forty patients (75%) had one or more CNAs abnormalities, including deletions or duplications. p-STAT5 was detected in 6/7 (85.7%) patients with IKZF1 deletion. Higher day 42 MRD was significantly associated with IKZF1 deletion (p = 0.04). Adult patients with positive p-STAT3, p-STAT5, and/or CRLF2 overexpression had shorter overall survival (P < 0.01) and disease-free survival (P < 0.001). CONCLUSION: The expression of p-STAT5 and/or CRLF2 is probably associated with dismal prognosis in adults. A combined assessment of CRLF2, p-STAT5, and CNAs might identify a high-risk subset of ALL, potentially encompassing Ph-like ALL.