pSTAT3/pSTAT5 Signaling Patterns in Molecularly Defined Subsets of Myeloproliferative Neoplasms.
BCR/ABL1-negative myeloproliferative neoplasms (MPNs) are characterized by recurrent mutations in JAK2, CALR, and MPL, each of which has been reported to alter JAK/STAT signaling pathways. This report characterizes JAK/STAT signaling patterns in molecularly defined subsets of MPN utilizing immunohistochemistry for pSTAT3 and pSTAT5. Analysis of 30 BCR/ABL1-negative, nonpolycythemia vera MPN identified 15 (50%) with JAK2 V617F, 2 with MPL mutations (7%), and 8 with CALR mutations (27%). All mutations were mutually exclusive, except for 1 case with concurrent JAK2 V617F and CALR mutations. pSTAT3 staining in megakaryocyte nuclei was found in 4 cases (13%) and was not significantly associated with mutation status. pSTAT5 staining in megakaryocyte nuclei was found in 16 cases (53%), as was significantly associated with JAK2 V617F versus CALR mutation (P=0.009). Erythroid staining for pSTAT5 was seen exclusively in "triple-negative (TN)" cases lacking JAK2 V617F, MPL, and CALR mutations (P=0.006, TN vs. other genotypes), and pSTAT5 staining in megakaryocyte nuclei was seen in 2 TN cases. pSTAT5 staining in TN MPN suggests that other unknown abnormalities in this pathway may contribute to the pathogenesis of these cases. Furthermore, the demonstration of distinct STAT staining patterns in molecularly defined MPN suggests that these mutations result in divergent signaling events that may contribute to the biological and prognostic differences in these molecular subsets of MPN.
Department of Laboratory Medicine, Cleveland Clinic, Cleveland, OH.
Hany
H
Sakr
Kelli
K
Clark Schneider
Gurunathan
G
Murugesan
Juraj
J
Bodo
Eric D
ED
Hsi
James R
JR
Cook
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D037282:Calreticulin / Q000235:genetics; D005260:Female; D016313:Genes, abl; D019337:Hematologic Neoplasms / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D053614:Janus Kinase 2 / Q000235:genetics; D008297:Male; D008533:Megakaryocytes / Q000502:physiology*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009196:Myeloproliferative Disorders / Q000235:genetics; D053628:Receptors, Thrombopoietin / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D055815:Young Adult
C576483:CALR protein, human; D037282:Calreticulin; D053628:Receptors, Thrombopoietin; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; C082218:MPL protein, human; C507924:JAK2 protein, human; D053614:Janus Kinase 2