Understanding Splenomegaly in Myelofibrosis: Association with Molecular Pathogenesis

Abstract

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.

Keywords: extramedullary hematopoiesis; myelofibrosis; splenomegaly.

Figure 1

Splenic extramedullary hematopoiesis in myelofibrosis. Cooperation between JAK2 signaling and C-X-C motif chemokine ligand 12 (CXCL12)/C-X-C chemokine receptor type 4 (CXCR4) axis activates downstream signal transducer and activator of transcription (STAT), phosphatidylinositol-3-kinase (PI3K/AKT), and RAS/MAPK pathways, leading to clonal expansion of hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) in the bone marrow. Moreover, it encourages the transfer and engraftment of the HSCs and HPCs to the spleen.