The present Perspective would focus on exciting treatment strategies under development for WM patients, such as proteasome inhibitors (e.g., ixazomib), BTK inhibitors (e.g., acalabrutinib, zanubrutinib, vecabrutinib), BCL2 inhibitors (e.g., venetoclax), and anti-CXCR4 antibodies (e.g., ulocuplumab), among others.
Our findings demonstrate that induction of ibrutinib resistance in WM cells can arise independent of BTK<sup>C481S</sup> and CXCR4<sup>WHIM-like</sup> mutations and sustained pressure from ibrutinib appears to activate compensatory AKT signaling as well as reshuffling of Bcl-2 family proteins for maintenance of cell survival.
This paper presents a rare case of WM with mutations positive for MYC and BCL2, making it a case of double hit B-cell lymphoplasmacytic lymphoma with plasmatic differentiation without morphological transformation to aggressive histology like DLBCL.
Three WM cell lines expressed pro-apoptotic Bcl-2 family members Bim or Bax and Bak at low levels, which determined their sensitivity to inducers of intrinsic apoptosis.
On the basis of evidence that the pro-inflammatory cytokine, interleukin 6 (IL6), and the survival-enhancing oncoprotein, B cell leukemia 2 (BCL2), have critical roles in the natural history of WM, we hypothesized that the enforced expression of IL6 and BCL2 in mice unable to perform immunoglobulin class switch recombination may result in a lymphoproliferative disease that mimics WM.
Thus, we investigated the anti-tumour effects of a pan-BCL2 inhibitor, AT-101, which has high binding specificity for BCL2 and MCL1 in preclinical models of plasma cell cancers (Multiple myeloma and Waldenström macroglobulinaemia).
NFkappaB activation may inhibit apoptosis through the transactivation of genes such as Bcl-2 and may therefore be an important mechanism in indolent lymphoproliferative disorders, including WM.
Bcl-2 downregulation via G3139 antisense treatment may have potential anticancer efficacy in WM and further studies to address its effects on clinical specimens are warranted, in anticipation of using this agent in WM clinical trials.
Accelerated plasmacytomagenesis in strain C.BCL2 may be useful for designing and testing BCL2 inhibition strategies in human plasma cell tumors overexpressing BCL2, such as Waldenström's macroglobulinemia and multiple myeloma.