Many chronic lymphocytic leukemia antibodies bind apoptotic cells with exposed non-muscle myosin heavy chain IIA in a similar manner as natural antibodies (101.13)

Abstract

Abstract Chronic lymphocytic leukemia (CLL) mAbs containing an IGHV1-69, IGHD3-16 and IGHJ3 rearrangement with a nearly identical or stereotyped sequence (subset 6) recognize non-muscle myosin heavy chain IIA (MYHIIA). Immunohistochemistry showed that MYHIIA becomes exposed on the surface of apoptotic cells. Flow cytometry with 7-amino-actinomycin D and Annexin V-Phycoerytherin showed that MYHIIA exposure (and concomitant subset 6 CLL mAb binding) occurs in a subgroup of both early and late apoptotic cells. Because other CLL mAbs bind apoptotic cells, the binding of MYHIIA exposed apoptotic cells (MEACs) to a panel of CLL mAbs, only two from subset 6, was measured by flow cytometry. Most CLL mAbs (16/26) bound MEACs well. The MEAC binding level inversely correlated with the degree of IGHV mutation. CLL patients with unmutated IGHV (≤ 2%) tend to have shorter survival times. Similarly, CLL mAbs with high binding to MEACs correlated with shorter patient survival. Natural antibodies are characterized by unmutated IGHV and binding to apoptotic cells. Thus, binding of normal serum antibodies to MEACs was tested. Serum samples had reactivities comparable to CLL mAbs with high binding to MEACs, whereas an antigen-selected human antibody specific for CD20 had little MEAC reactivity. Thus, many CLL leukemic clones may derive from natural antibody-expressing B cells, such as B-1 cells, and stimulation by MEACs could lead to development and/or expansion of CLL leading to poor patient outcome.