IL-4, IgM, and resistance to BTKi and PI3Kδi in CLL

Abstract

In this issue of Blood, Aguilar-Hernandez et al1 refine our understanding of the mechanism of action of interleukin 4 (IL-4) in promoting B-cell receptor (BCR)-mediated signaling in primary human chronic lymphocytic leukemia (CLL) and resistance to a Bruton tyrosine kinase inhibitor (BTKi), ibrutinib and a phosphatidylinositol 3-kinase δ inhibitor (PI3Kδi), idelalisib. The tumor microenvironment is firmly established as providing stimuli to cause CLL cells residing in the lymph nodes or bone marrow to proliferate, survive, and resist chemotherapy as demonstrated by animal models, which suggests a requirement for T cells2 and stromal cells,3 whereas immunohistochemistry has shown close connections between leukemic B cells and T cells in lymph node proliferation centers. As well as direct cell:cell contacts, growth factors, including IL-4, and chemokines are also important modes of communication between the microenvironment and the leukemic cell. Many of these soluble factors are produced in T cells, and the CD4+ T-cell subset, the follicular helper T-cell subset, and TH2 cells may be particularly important in producing IL-4.