Mutations of the SHP-2 Proteine Tyrosine Phosphatase in Adult Patients with Acute Myeloid Leukemia.

Acute myeloid leukaemia (AML) represents a heterogeneous group of early stem cell malignancies characterized by an uncontrolled expansion of malignant cells blocked at certain stages of myeloid differentiation. Several genetic abnormalities have been described, including translocations involving genes of the CBF family, as well as activating mutations of signal transduction proteins, e.g. N-RAS, K-RAS or the Flt3- receptor tyrosine kinase (RTK). More recently, mutations in the SHP-2 protein, a tyrosine phosphatase involved in RTK signal transduction, have been described in patients with juvenile myelomonocytic leukaemia (JMML) as well as paediatric patients with AM. Only limited data on this aberration are available in older patients. In order to investigate the prevalence and the prognostic relevance of this gene in adults, we analyzed the mutational status of SHP-2 in a cohort of patients with AML.

Patients and Methods: DNA samples prepared from bone marrow or peripheral blood samples taken at diagnosis from 977 patients treated in the AML96 protocol of the SHG Dresden were analyzed. Screening for mutations in the mutational hot spot in exon 3 of the PTPN11 gene coding for SHP-2 was performed on a dHPLC system (Transgenomic). Samples with aberrant dHPLC chromatogram were sequenced.

Results: In the 977 patients investigated so far, 29 PTPN11 exon 3 mutations were found (3%). All mutations consisted of single base pair exchanges in codons 60–76, mostly affecting codons 69 (n=6), 72 (n=7) and 76 (n=6). Patients with PTPN11 mutations were more likely to have FAB M0 (p= .038) or M5b (p=.045) morphology than negative cases and had a significantly lower prevalence of FLT3-ITD mutations (p= .017). PTPN11 mutations were associated with a normal karyotype in 15/28 evaluable patients, whereas 13 had cytogenetic abnormalities, all of which were either high risk (−7/7q-, n=4; inv3, n=2, complex, n=2, −5, n=1) or intermediate risk (n=4) aberrations. No significant differences were found in the complete remission rate as well as the overall and event free survival, but a trend for a shorter disease free survival was observed in patients with PTPN11 mutations (median 7.8 vs 14.4; p= 0.06) associated with a significantly increased rate of relapse (p= .02). Although not significant yet, a similar trend was seen for patients with normal karyotype.

Conclusion: PTPN11 mutations can be found in a small but considerable number of adult patients with AML. Consistent with the data in children, this mutation seems to more prevalent in patients with monosomy 7 and leukemias with monocytic differentiation. Although very preliminary, the data point to a worse prognosis of patients with SHP-2 mutations. We are currently further extending the number of patients and analyze additional exons to delineate the potential prognostic role of this aberration.