Functionally Relevant Cytokine/Receptor Axes in Myelofibrosis

Abstract

Dysregulated inflammatory signaling is a key feature of myeloproliferative neoplasms (MPNs), most notably of myelofibrosis (MF). Indeed, MF is considered the prototype of onco-inflammatory hematologic cancers. While increased levels of circulatory and bone marrow cytokines are a well-established feature of all MPNs, a very recent body of literature is intriguingly pinpointing the selective overexpression of cytokine receptors by MF hematopoietic stem and progenitor cells (HSPCs), which, by contrast, are nearly absent or scarcely expressed in essential thrombocythemia (ET) or polycythemia vera (PV) cells. This new evidence suggests that MF CD34⁺ cells are uniquely capable of sensing inflammation, and that activation of specific cytokine signaling axes may contribute to the peculiar aggressive phenotype and biological behavior of this disorder. In this review, we will cover the main cytokine systems peculiarly activated in MF and how cytokine receptor targeting is shaping a novel therapeutic avenue in this disease.

Keywords: CD34+ cells; cytokine receptors; hematopoietic niche anatomy; inflammation; myelofibrosis; myeloproliferative neoplasms.

Figure 1

The “perfect storm” that leads to the end-stage disease in MPNs. In normal bone marrow, cytokine levels are low and hematopoietic stem cells do not express cytokine receptors. In PV/ET bone marrow, cytokines levels are high but clonal hematopoietic stem cells express no or low levels of cytokine receptors. In the MF bone marrow, cytokines are high, and the MF clone overexpresses cytokine receptors (IL-1, CXCL8, CCL2, and IL-13 receptors). The activation of these cyto/chemokine axes triggers pro-proliferative and pro-survival signals that boost the clonal expansion and release of additional pro-inflammatory mediators, generating the vicious cycle leading to the “burn out” and “spent phase” with fibrosis, BM anatomical subversion, and high risk of leukemic evolution.