Abstract
Pharmacological targeting of BTK using ibrutinib has recently shown encouraging clinical activity in a range of lymphoid malignancies. Recently we reported that ibrutinib inhibits human acute myeloid leukemia (AML) blast proliferation and leukemic cell adhesion to the surrounding bone marrow stroma cells. Here we report that in human AML ibrutinib, in addition, functions to inhibit SDF1/CXCR4-mediated AML migration at concentrations achievable in vivo. It has previously been shown that SDF1/CXCR4-induced migration is dependent on activation of downstream BTK in chronic lymphocytic leukaemia (CLL) and multiple myeloma. Here we show that SDF-1 induces BTK phosphorylation and downstream MAPK signalling in primary AML blast. Furthermore, we show that ibrutinib can inhibit SDF1-induced AKT and MAPK activation. These results reported here provide a molecular mechanistic rationale for clinically evaluating BTK inhibition in AML patients and suggests that in some AML patients the blasts count may initially rise in response to ibrutinib therapy, analgous to similar clinical observations in CLL.
Highlights
Despite recent significant progress in the understanding of the biology of acute myeloid leukemia (AML) the clinical outcomes for the majority of patients diagnosed with AML presently remain poor
We initially examined the expression of CXCR4 in human AML cell lines and found that 4/4 cell lines were positive for CXCR4 expression (Figure 1A)
Since SDF1 has been shown to mediate migration of AML in a CXCR4 dependent mechanism and that SDF1/CXCR4-induced migration is dependent on activation of downstream Bruton’s Tyrosine Kinase (BTK) in chronic lymphocytic leukemia (CLL), myeloma and normal B cells [21, 27], we examined the activity of BTK phosphorylation and downstream AKT and MAPK in response to SDF1 and found that SDF1 increases levels of pBTK and downstream MAPK in primary AML blasts (Figure 2A)
Summary
Despite recent significant progress in the understanding of the biology of AML the clinical outcomes for the majority of patients diagnosed with AML presently remain poor. Recent phase 1, 2 and 3 studies of the irreversible oral BTK inhibitor, ibrutinib have demonstrated excellent clinical activity and tolerability against a variety of B-cell malignancies including, chronic lymphocytic leukemia (CLL), mantle cell lymphoma, hairy cell leukaemia and diffuse large B-cell lymphoma in younger and older patients alike [8,9,10,11,12,13,14,15,16]. Our recent study described for the first time that ibrutinib and BTK-targeted RNA interference reduced www.impactjournals.com/oncotarget factor-induced proliferation of both AML cell lines and primary AML blasts, as well as reducing AML blast adhesion to BMSC [19]
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