Studies on chronic lymphocytic leukemia (CLL) and B-cells their signal pathways


Studies on molecular targets of CLL antibodies.

CLL is the most frequent leukemia in the West and it has a heterogeneous appearance. The finding that there are multiple subsets of CLL with stereotyped immunoglobulin (Ig) heavy-and light-chain complementarity diversity region 3 (CDR3) have explicitly brought the question of antigen-specificity to the cutting edge within the CLL field.

We reported a novel finding on the highly resticted and biased specificities of CLL Abs some years ago, showing limited target structures for the CLL Abs, which were exposed on oxidized-LDL, apoptotic cells, and bacteria (Lanemo Myhrinder et al Blood 2008 och Bergh et al Hematologica 2014). Together with parallel findings that bacterial lung infections increases the risk of CLL, our data supports the hypothesis that bacterial infections in synergy with neo-self antigen/apoptotic cells may drive promotion of CLL by continuously triggering the B-cell receptors (allowing ongoing proliferatin) thus making the B-cell population vulnerable to tumor transforming events such as mutations.

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Studies on CLL-cell microenvironment

CLL cells do not proliferate in the blood, but in lymph nodes and bone marrow in so called proliferative centers (pseudo follicles). Stromal cells surrounding the CLL cells have a nursing role and feed the CLL cells with growth factors such as thioredoxin (Trx), which is a redox-regulatory protein protecting CLL cells from apoptosis in vitro (Nilsson J et al Blood 2000) and in the in vivo microenvironment (Bäckman et al Hematologica 2007).

Trx produced by purified stromal cells rescued CLL cells from apoptosis thru oxidative stress e.g. ROS. Trx and protein disulphide isomerase (PDI), which belong to the Trx-superfamily, regulate via redox-reactions the membranerecptro TNFR2 (Söderberg et al Antiox Redox Signal 2013).

CLL cells are activated by DNA-sensors via a recently discovered signal pathway

CLL cells resemble the B1 B-cells belonging to the innate first-line defense. We have recently found that certain modified DNA-sequences found in microbes are prompt cell triggers upon binding DNA-sensors on CLL cell surfaces. This signal pathway generate release of chromatin fibers that resembles traps (Ingelsson et al 2015 manuscript).

Foto: Thor Balkhed

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