Monday, October 17, 2011

The role of CD38 in affecting CLL migration

In vitro activation of CD38 caused by stimulating mAbs induces a portion of the CLL clone (10%-30%) to proliferate, giving rise to an immunoblast-like component that does not secrete Igs; these effects are dependent on significant amounts of soluble IL-2, in keeping with the observation that T lymphocytes and accessory cells are needed in vivo. This was a first indication that CD38 transduces signals, leading or contributing to CLL cell growth, even in the absence of stimuli coming from the BCR.

First indications that CD38 acts as a molecular signpost that routes leukemic cells to specialized niches arose from in vivo findings that the number of CD38 molecules expressed in BM and LN is higher than in circulating lymphocytes. In addition, nurse-like cells, differentiated in vitro from circulating CD14+ cells and also presumably present in solid lymphoid tissues in vivo, express CD31, the CD38 ligand. Interactions between CD38 and CD31 in this system promote proliferation and survival through a molecular circuit that can be interrupted by blocking anti-CD31 or anti-CD38 mAbs. CD38/CD31 interaction results in a genetic signature that includes more than 1500 modulated sequences. Pathway analysis drastically reduces this complexity, with proliferation and migration emerging as the main elements characterizing this receptor/ligand system.

CD38 signaling may be influenced by the presence of ZAP-70. Patients with CD38+ZAP-70+ clones are more responsive to activation of intracellular proteins than CD38+ZAP-70− persons. This may explain why the simultaneous expression of the two molecules offers a more efficient identification of the high-risk patient subset. CD38+ZAP-70+ CLL cells also migrate better in response to the CXCL12 chemokine and exhibit a genetic signature primarily consisting of genes involved in cell locomotion. A functional cooperation between CD38 and CXCR4 was demonstrated by showing that binding of stimulating anti-CD38 mAbs and de novo expression of CD38 by lentiviral infection increases chemotaxis in response to CXCL12.

These effects on proliferation and chemotaxis are altered by blocking reagents, which interfere with CXCL12-mediated migration in vitro and block CLL homing in an NOD/SCID mouse model. A possible explanation is that CD38 and CXCR4 are associated on the same membrane patches; and hence, stimulating and blocking anti-CD38 mAbs have the potential to interfere positively or negatively with CXCL12 binding to the CXCR4 receptor, changing responses. Recent data indicate that this signaling platform of molecules is more complex and includes adhesion molecules, such as CD49d and matrix metalloproteases, such as MMP-9.

10 comments:

Anonymous said...

How do mutated or unmutated immunoglobulin variable region heavy chain (IgVH) genes relate, if at all, to CD 38?

Good to see you back at the computer! Go for a walk today!

Anonymous said...

Dear Dr.Hamblin,
My CLL type is unmutated with both CD38 and ZAP-70 negative. Why do these discrepancies happen in the markers (are they frequent?) and does any of them override the others (I mean mutational status versus CD38 and ZAP-70). Should we look at just the mutational status?
Thank you!

Terry Hamblin said...

33% are mutated and CD38 negative. 33% are unmutated and CD38 positive and 33% are discordant.

Terry Hamblin said...

ZAP-70 is unreliable. CD38 is discordant with IGHV mutations in a third of cases.

Anonymous said...

ok, if discordant, does CD38- somehow help the unmutated case?

Terry Hamblin said...

Discordant cases have an intermediate prognosis.

Stew (WORCESTER) UK said...

Good morning Terry , i hope you are feeling better just wanted to know your views on green tea extracts (1000mg daily) (EGCG) my close been taking the capsules for six weeks and nodes in his neck has virtually disappeared , he is currently on the watch and wait while this may be just a coincidence what are your thoughts on EGCG ? Due to have more blood tests shortly (FBC)

Terry Hamblin said...

EGCG undoubtedly has a minor therapeutic effect in shrinking nodes and lowering white counts, but this is generally in patients who are on watch and wait who do not require treatment under international guidelines.

Stew (WORCESTER) UK said...

Thank you for taking the time to respond just through nurse training so only know the basic of physiology and anatomy , let alone chemistry but how is it able to lower the white blood count and reduce nodes EGCG compound some how destroy some of the mutant B cells ?
I really do appreciate your time and yes sorry this is on a very basic level
Stew

Terry Hamblin said...

I can't remember the biochemistry, but I have written on it before and you will find a lot if you Google green tea. There was a Mayo Clinic Trial which established that it does have an effect, but it is not an effect worth spending all that money on.