Production of Blood Cells

What controls the production of bone marrow cells?

There are very many chemicals that stimulate the production of blood cells; they go under the general name of cytokines. Different lineages of the blood are stimulated by different cytokines.

Red cells are stimulated by erythropietin or EPO. If you lose a pint of blood, your kidneys make more EPO and this makes your bone marrow make more red cells. Does this affect other lineages? In particular, does it stimulate the lymphocytes? No it doesn't. Many people take EPO when they are having treatment for their CLL, and when you have a pint taken off it's the same EPO that stimulates the production of red cells. It does not make the CLL cells grow.

There are similar substances that make other lineages grow. Best known is G-CSF which makes granulocytes recover after chemotherapy. This is also available as a drug called Neupogen. This doesn't make CLL cells grow either.

July 2005

I have just written a review mainly about ZAP-70, but it included a section
on the North Shore results. This is what I wrote.
Proliferation
In the circulating blood there are only a small number of 'proliferating'
cells denoted by positive Ki67 staining [1], but ethidium bromide staining
showed these to be in G1 and not in S phase. Cordone et al [2] showed a close
correlation between the number of cells expressing Ki67 and advanced clinical
stage, while Del Giogli et al similarly correlated the expression of
proliferating cell nuclear antigen (PCNA) with clinical stage and lymphocyte doubling
time [3].
Proliferation takes place in CLL, not among the circulating cells, but in
the proliferation centers, and the numbers of these correlated quite well with
the lymphocyte doubling time [4]. Unfortunately, few CLL patients have lymph
node biopsies. Early attempts at measuring lymphocyte kinetics in CLL used
techniques that were open to criticism, had small numbers of cases and got the
wrong answer according to what was believed at the time [5-8].
However, the idea that CLL cells have inconsequential levels of cell
division has been exploded by experiments by Messmer et al [9] using an in vivo
stable isotope labeling technique. They administered heavy water (2H2O) orally
for 84 days in order to incorporate deuterium into the deoxyribose moiety of
newly divided CLL cells which could be measured by gas chromatography/mass
spectroscopy. They established that CLL cells had a birth rate of between 0.1%
and >1% of the total leukemic clone every day. Those patients with birth rates
of >0.35% per day had more active and progressive disease than those with
lower birth rates. The more benign variants of CLL may well have a problem of
apoptosis as their major defect, but for the type that is of most concern to
the patients, the problem is one of uncontrolled proliferation.
References
1. ORCHARD JA, OSCIER DG: Prognostic value of Ki 67 and cell cycle
analysis in chronic lymphocytic leukaemia. Br J Haematol. (1996) 93:116.
2. CORDONE I, MATUTES E, CATOVSKY D: Monoclonal antibody Ki-67
identifies B and T cells in cycle in chronic lymphocytic leukaemia. Leukemia. (1992)
6:902-906.
3. DEL GIGLIO A, O’BRIEN S, FORD RJ JR et al: Proliferating cell
nuclear antigen (PCNA) expression in chronic lymphocytic leukaemia (CLL). Leuk
Lymphoma. (1993) 10:265-271.
4. PILERI SA, ASCANI S, SABATTINI E: The pathologist's view point. Part
I--indolent lymphomas. Haematologica. (2000) 85:1291-307.
5. ZIMMERMAN TS, GODWIN HA, PERRY S: Studies of leukocyte kinetics in
chronic lymphocytic leukemia. Blood. (1968) 31:277-91.
6. SCHIFFER LM, CHANANA AD, CRONKITE EP: Lymphocyte kinetics in chronic
lymphocytic leukaemia (CLL) studied by ECIB. Br J Haematol. (1969) 17:408.
7. SIMONSSON B, NILSSON K: 3H-thymidine uptake in chronic lymphocytic
leukaemia cells. Scand J Haematol. (1980) 24:169-73.
8. DORMER P, THEML H, LAU B: Chronic lymphocytic leukemia: a
proliferative or accumulative disorder? Leuk Res. (1983) 7:1-10.
9. MESSMER BT, MESSMER D, ALLEN SL et al: In vivo measurements
document the dynamic cellular kinetics of chronic lymphocytic leukemia B cells. J
Clin Invest. (2005) 115:755-64.
** This paradigm shifting paper makes it clear that the main problem in
CLL is not failure of apoptosis, but uncontrolled proliferation
In fact the drugs that are used most frequently against CLL, chlorambucil,
cyclophosphamide and fludarabine, are directed against dividing cells.
Recently there have been trials of agents like Bcl-2 anti-sense that are directed
against the anti-apoptotic mechanisms, but they have not proved clinically very
useful.