SHP-1 expression in chronic myeloid leukemia: clinical significance and impact on response to imatinib treatment

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Abstract

Background

SH2-containing tyrosine phosphatase (SPH-1) is a negative regulator of protein tyrosine kinases and is also a tumor suppressor that is physically and functionally linked to BCR-ABL, the hallmark for pathogenesis, diagnosis, and targeted therapy in chronic myeloid leukemia (CML).

Aim

This study aimed at investigating the levels of SHP-1 mRNA during chronic phase (CP), accelerated phase (AP), and blast phase (BP) CML and also assessing its impact on the response of CP-CML patients to imatinib mesylate (IM) therapy.

Patients and methods

The study was carried out on 77 newly diagnosed CML patients (56 CP, 13 AP, and eight BP). Ten age-matched and sex-matched volunteers free from any hematological or nonhematological malignancies served as the control group. Patients were diagnosed and classified into appropriate phases according to the WHO criteria by clinical and radiological examination, cytomorphological analysis, neutrophil alkaline phosphatase scoring, conventional cytogenetic analysis, FISH for t(9; 22) and real-time quantitative PCR analysis for BCR-ABL fusion transcripts. CP patients received IM therapy and were followed up for assessment of the response to treatment. SHP-1 mRNA levels were measured at diagnosis using real-time quantitative PCR.

Results

SHP-1 levels were highly significantly increased in CP-CML patients (5.8–538; median 48.1) compared with normal controls (2.6–8.3; 5.2) and patients presenting with AP (2.1–168; 13.8) or BP (1.9–173; 12.3) (P<0.01). The levels were not correlated with the patients’ clinical or laboratory data. Follow-up of CP-CML patients on IM therapy revealed that patients with lower baseline SHP-1 levels were less likely to achieve a major molecular response at 18 months compared with those with higher levels. SHP-1 was highly significantly elevated in optimal responders compared with suboptimal responders and those who failed treatment (12.1–538; 63.2 vs. 5.8–177; 15.1) (P<0.01); these levels not being correlated to the Sokal risk score.

Conclusion

SHP-1 mRNA expression is downregulated in patients with more progressive CML. Moreover, determining the SHP-1 levels at diagnosis can provide a biological predictor of the IM response in patients with CP-CML.

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