Patterns of Expression of SHP-1 and JAK-2p in Myelodysplastic Syndromes: A Potential New Prognostic Factor.

The protein-tyrosine-phosphatase (PTPase) SHP-1 is expressed almost exclusively in hematopoetic cells. Most growth factor receptors rely on the Jak/Stat pathway for intracellular transduction, to drive specific gene expression which are involved in cell proliferation and differentiation. Abnormal signaling in some of these pathways has been linked to hematopoietic malignancies, like the ALL tel-Jak2 gene fusion. In some other cases activation is mediated by kinases not normally associated with Stats, like abl. Recently several authors have linked dysregulation of PTPases, especially SHP-1, to non-Hodgkin lymphoma, familial polycythemia, chronic neutropenia and AML. There are no reports on expression of SHP-1 in myelodysplastic syndromes. Here we hypothesize that SHP-1 downregulation may play a role in the leukemic transformation of myelodysplastic syndromes and may impact survival. Retrospectively, from January 1990 to January 2004, we studied 45 patients (29 men, 16 women; median age 70 yrs) with myelodysplastic syndromes (5 RA, 3 RAS, 3 RCMD, 9 RAEB-I, 11 RAEB-II, 2 5q-, 2 Unclass, 3 AML, 6 SMDS). Bone marrow biopsies were examined from each patient. 5 μm sections were dewaxed, heated for antigen retrieval in sodium citrate buffer, and immunostained by routine methods. Antibodies against SHP-1 and Jak-2p were purchased from Santa Cruz Biotechnology (Santa Cruz, CA) and Cell Signaling (Beverly, MA) respectively. SHP-1 and Jak-2p expression were evaluated on bone marrow samples as a percentage of positive cells. A percentage between 33 and 66 was considered normal for SHP-1 expression. Jak-2p positivity was defined as normal, if less or equal to 50 % of cells stained positively. Ranges of normal values were derived from healthy controls. With a median follow-up of 65 months, 13 (28%) showed disease progression, 9 of them towards AML. Median OS and EFS were 15 and 12 months respectively. 25 patients have died, mostly of disease related complications. The U-Mann-Whitney test comparing means between patients that progressed and those that did not was only significant (p<0.05) for hemoglobin and erythropoietin levels at diagnosis. A χ² test failed to detect any qualitative variable at diagnosis associated with progression: only number of platelets and erythroid dysplasia approached statistical significance. Kaplan-Meier analysis showed that TTP was significantly shorter among those with less cytopenias (p=0.023) and previous history of radiation and/or chemotherapy (p=0.034). Overall survival was also worse among those with previous history of radiation and/or chemotherapy (p=0.009), high risk cytogenetics according to IPSS (p<0.001), lower expression of SHP-1 (p=0.03) or a combination of higher expression of Jak-2p plus lower expression of SHP-1 (p=0.0517). Interestingly none of the commonly accepted prognostic methods for MDS (IPSS, FAB or WHO) showed statistical significance in OS in this analysis. In conclusion, immunostaining of SHP-1 of bone marrow biopsies at diagnosis may be a new prognostic marker for MDS patients.