Myelofibrosis (MF) is a clinical manifestation of chronic BCR-ABL1-negative 
chronic myeloproliferative neoplasms. Splenomegaly is one of the major clinical 
manifestations of MF and is directly linked to splenic extramedullary 
hematopoiesis (EMH). EMH is associated with abnormal trafficking patterns of 
clonal hematopoietic cells due to the dysregulated bone marrow (BM) 
microenvironment leading to progressive splenomegaly. Several recent data have 
emphasized the role of several cytokines for splenic EMH. Alteration of 
CXCL12/CXCR4 pathway could also lead to splenic EMH by migrated clonal 
hematopoietic cells from BM to the spleen. Moreover, low Gata1 expression was 
found to be significantly associated with the EMH. Several gene mutations were 
found to be associated with significant splenomegaly in MF. In recent data, 
JAK2V617F homozygous mutation was associated with a larger spleen size. In other 
data, CALR mutations in MF were signigicantly associated with longer larger 
splenomegaly-free survivals than others. In addition, MF patients with ≥1 
mutations in AZXL1, EZH1 or IDH1/2 had significantly low spleen reduction 
response in ruxolitinib treatment. Developments of JAK inhibitors, such as 
ruxolitinib, pacritinib, momelotinib, and febratinib enabled the effective 
management in MF patients. Especially, significant spleen reduction responses of 
the drugs were demonstrated in several randomized clinical studies, although 
those could not eradicate allele burdens of MF.