Many chronic lymphocytic leukemia antibodies recognize apoptotic cells with exposed nonmuscle myosin heavy chain IIA: implications for patient outcome and cell of origin

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BlankBlood, 13 May 2010, Vol. 115, No. 19, pp. 3907-3915.

Prepublished online as a Blood First Edition Paper on January 28, 2010; DOI

10.1182/blood-2009-09-244251.

Many chronic lymphocytic leukemia antibodies recognize apoptotic cells with

exposed nonmuscle myosin heavy chain IIA: implications for patient outcome and

cell of origin

C. Chu13, Catera1, Lu Zhang1, Sebastien Didier1, a M.

Agagnina1, Rajendra N. Damle1,3, S. Kaufman2, E. Kolitz13,

L. 1,2,4, Kanti R. Rai1,2,4, and Chiorazzi1,2,4,5

1 The Feinstein Institute for Medical Research, North Shore–Long Island Jewish

(LIJ) Health System, Manhasset, NY; 2 Department of Medicine, North Shore

University Hospital and Long Island Jewish Medical Center, North Shore–LIJ

Health System, Manhasset and New Hyde Park, NY; 3 Department of Medicine, New

York University School of Medicine, NY; 4 Department of Medicine, Albert

Einstein College of Medicine, Bronx, NY; and 5 Department of Cell Biology,

Albert Einstein College of Medicine, Bronx, NY

Many B-cell chronic lymphocytic leukemia (CLL) monoclonal antibodies (mAbs) can

be grouped into subsets based on nearly identical stereotyped sequences. Subset

6 CLL mAbs recognize nonmuscle myosin heavy chain IIA (MYHIIA). Herein, we

report that during apoptosis, MYHIIA becomes exposed on the cell surface of a

subgroup of apoptotic cells, allowing subset 6 CLL mAbs to bind with it. Because

other non–subset 6 CLL mAbs interact with apoptotic cells, 26 CLL mAbs,

including 24 not belonging to subset 6, were tested for reactivity with

MYHIIA-exposed apoptotic cells (MEACs). More than 60% of CLL mAbs bound MEACs

well; most of these mAbs expressed unmutated IGHV (15 of 16) and belonged to a

stereotyped subset (14 of 16). Binding to MEACs inversely correlated with the

degree of IGHV mutation. Interestingly, high binding to MEACs significantly

correlated with poor patient survival, suggesting that the basis of IGHV

mutation status as a CLL prognostic factor reflects antigen binding. Finally,

natural antibodies from human serum also reacted with MEACs. Taken together, our

data indicate that a large proportion of CLL clones emerge from natural

antibody-producing cells expressing immunoglobulins that recognize MEACs, and

that this reactivity is associated with poor clinical outcome.