Other candidates for prognostic markers
In addition to the more extensively studied prognostic markers discussed in the Review, many
molecular and biological factors have been described to correlate with an adverse outcome in patients
with chronic lymphocytic leukemia (CLL).1,2 A detailed assessment of these factors is beyond the
scope of this Review, and we apologize to all authors of these articles that their work cannot be cited
because of space limitations.
The different molecules and factors include the proangiogenic molecule VEGF,3,4 soluble CD44,5–7
soluble CD26,8,9 circulating CD20,10 and CD49d,11,12 as well as insulin-like growth factor 1,13 matrix
metalloproteinase 9,14,15 Bcl2,16–20 T-cell leukemia 1,21 and soluble intracellular adhesion molecule
1.22–25 Other candidates for prognostic markers in CLL are short telomere length 26–29 and high
telomerase activity,29–31 expression of myeloid cell leukemia sequence 1,32 activation-induced cytidine
deaminase mRNA33 and hematopoietic lineage cell-specific protein 1,34 as well as a higher level of
circulating endothelial cells.35 In addition, the expression of lipoprotein lipase and ADAM29,36–38
overexpression of TOSO39 and PEG1O,40 as well as CLLU1 expression41,42 and RelA DNA binding43
were all associated with rapid disease progression or impaired overall survival. Furthermore, the
cytokines interleukin (IL)-622,44,45 IL-846,47 and IL-1044 and tumor necrosis factor-α48 could potentially
serve as novel serum markers.
The area of research on epigenetic markers and microRNAs led to the unexpected and fascinating
discovery of an interplay between protein-coding genes and noncoding RNAs, that was found to be
causally involved in cancer initiation, progression, dissemination, and chemotherapy resistance.49,50
These microRNAs might not only be causal in the pathogenesis of CLL, but could also explain the
predictive value of a variety of prognostic markers. For instance, a low expression of miR-29c and
miR-223 was found to correlate with the two adverse prognostic factors ZAP70 and lipoprotein lipase
and to be associated with an inferior treatment-free survival and overall survival.51
This large number of prognostic factors needs further investigation and a systematic comparison to
other factors in larger clinical cohorts in order to assess the true prognostic and clinical value of these
markers with regards to survival.
1. Böttcher, S. et al. Standardized MRD flow and ASO IGH RQ-PCR for MRD quantification in CLL patients after
rituximab-containing immunochemotherapy: a comparative analysis. Leukemia 23, 2007–2017 (2009).
2. Sah, S. P., Matutes, E., Wotherspoon, A. C., Morilla, R. & Catovsky, D. A comparison of flow cytometry, bone
marrow biopsy, and bone marrow aspirates in the detection of lymphoid infiltration in B cell disorders. J. Clin.
Pathol. 56, 129–132 (2003).
3. Molica, S., Vitelli, G., Levato, D., Gandolfo, G. M. & Liso, V. Increased serum levels of vascular endothelial
growth factor predict risk of progression in early B-cell chronic lymphocytic leukaemia. Br. J. Haematol. 107,
605–610 (1999).
4. Shanafelt, T. D. et al. Pretreatment angiogenic cytokines predict response to chemoimmunotherapy in patients
with chronic lymphocytic leukaemia. Br. J. Haematol. 146, 660–664 (2009).
5. Eisterer, W. et al. Elevated levels of soluble CD44 are associated with advanced disease and in vitro
proliferation of neoplastic lymphocytes in B-cell chronic lymphocytic leukaemia. Leuk. Res. 28, 1043–1051
(2004).
6. Molica, S., Vitelli, G., Levato, D., Giannarelli, D. & Gandolfo, G. M. Elevated serum levels of soluble CD44 can
identify a subgroup of patients with early B-cell chronic lymphocytic leukemia who are at high risk of disease
progression. Cancer 92, 713–719 (2001).
7. Zarcone, D. et al. Functional and clinical relevance of CD44 variant isoform expression on B-cell chronic
lymphocytic leukemia cells. Haematologica 83, 1088–1098 (1998).
8. Cro, L. et al. CD26 expression in mature B-cell neoplasia: its possible role as a new prognostic marker in
B-CLL. Hematol. Oncol. 27, 140–147 (2009).
9. Molica, S. et al. Serum level of CD26 predicts time to first treatment in early B-chronic lymphocytic leukemia.
Eur. J. Haematol. 83, 208–214 (2009).
10. Manshouri, T. et al. Circulating CD20 is detectable in the plasma of patients with chronic lymphocytic leukemia
and is of prognostic significance. Blood 101, 2507–2513 (2003).
11. Gattei, V. et al. Relevance of CD49d protein expression as overall survival and progressive disease
prognosticator in chronic lymphocytic leukemia. Blood 111, 865–873 (2008).
12. Shanafelt, T. D. et al. CD49d expression is an independent predictor of overall survival in patients with chronic
lymphocytic leukaemia: a prognostic parameter with therapeutic potential. Br. J. Haematol. 140, 537–546
(2008).
13. Molica, S. et al. Serum insulin-like growth factor is not elevated in patients with early B-cell chronic lymphocytic
leukemia but is still a prognostic factor for disease progression. Eur. J. Haematol. 76, 51–57 (2006).
14. Molica, S. et al. Increased serum levels of matrix metalloproteinase-9 predict clinical outcome of patients with
early B-cell chronic lymphocytic leukaemia. Eur. J. Haematol. 70, 373–378 (2003).
15. Kamiguti, A. S. et al. The role of matrix metalloproteinase 9 in the pathogenesis of chronic lymphocytic
1
leukaemia. Br. J. Haematol. 125, 128–140 (2004).
16. Pepper, C., Bentley, P. & Hoy, T. Regulation of clinical chemoresistance by bcl-2 and bax oncoproteins in
B-cell chronic lymphocytic leukaemia. Br. J. Hematol. 95, 513–517 (1996).
17. Nückel, H. et al. Association of a novel regulatory polymorphism (-938C>A) in the BCL2 gene promoter with
disease progression and survival in chronic lymphocytic leukemia. Blood 109, 290–297 (2007).
18. Molica, S., Dattilo, A., Guilino, C., Levato, D. & Levato, L. Increased bcl-2/bax ratio in B-Cell chronic
lymphocytic leukemia is associated with a progressive pattern of disease. Haematologica 83, 1122–1124
(1998).
19. Robertson, L. E., Plunkett, W., McConnell, K., Keating, M. J. & McDonnell, T. J. Bcl-2 expression in chronic
lymphocytic leukemia and its correlation with the induction of apoptosis and clinical outcome. Leukemia 10,
456–459 (1996).
20. Faderl, S. et al. Expression profile of 11 proteins and their prognostic significance in patients with chronic
lymphocytic leukemia (CLL). Leukemia 16, 1045–1052 (2002).
21. Herling, M. et al. High TCL1 levels are a marker of B-cell receptor pathway responsiveness and adverse
outcome in chronic lymphocytic leukemia. Blood 114, 4675–4686 (2009).
22. Callea, V. et al. Clinical significance of sIL2R, sCD23, sICAM-1, IL6 and sCD14 serum levels in chronic
lymphocytic leukemia. Haematologica 81, 310–315 (1996).
23. Molica, S., Dattilo, A., Mannella, A., Levato, D. & Levato, L. Expression on leukemic cells and serum circulating
levels of intracellular adhesion molecule-1 (ICAM-1) in B-cell chronic lymphocytic leukemia: implications for
prognosis. Leuk. Res. 19, 573–580 (1995).
24. Musolino, C. et al. Circulating levels of intracellular adhesion molecule-1 (ICAM-1) and soluble interleukin 2
receptors (IL-2R) in patients with B cell chronic lymphocytic leukaemia. Riv. Eur. Sci. Med. Farmacol. 18,
113–118 (1996).
25. Christiansen, I., Gidlöf, C., Wallgren, A. C., Simonsson, B. & Tötterman, T. H. Serum levels of soluble
intercellular adhesion molecule 1 are increased in chronic B-lymphocytic leukemia and correlate with clinical
stage and prognostic markers. Blood 84, 3010–3016 (1994).
26. Rossi, D. et al. Telomere length is an independent predictor of survival, treatment requirement and Richter’s
syndrome transformation in chronic lymphocytic leukemia. Leukemia 23, 1062–1072 (2009).
27. Roos, G. et al. Short telomeres are associated with genetic complexity, high-risk genomic aberrations, and
short survival in chronic lymphocytic leukemia. Blood 111, 2246–2252 (2008).
28. Grabowski, P. et al. Telomere length as a prognostic parameter in chronic lymphocytic leukemia with special
reference to VH gene mutation status. Blood 105, 4807–4812 (2005).
29. Damle, R. N. et al. Telomere length and telomerase activity delineate distinctive replicative features of the
B-CLL subgroups defined by immunoglobulin V gene mutations. Blood 103, 375–382 (2004).
30. Terrin, L. et al. Telomerase expression in B-cell chronic lymphocytic leukemia predicts survival and delineates
subgroups of patients with the same IgVH mutation status and different outcome. Leukemia 21, 965–972
(2007).
31. Tchirkov, A. et al. hTERT expression and prognosis in B-chronic lymphocytic leukemia. Ann. Oncol. 15,
1476–1480 (2004).
32. Pepper, C. et al. Mcl-1 expression has in vitro and in vivo significance in chronic lymphocytic leukemia and is
associated with other poor prognostic markers. Blood 112, 3807–3817 (2008).
33. Heintel, D. et al. High expression of activation-induced cytidine deaminase (AID) mRNA is associated with
unmutated IGVH gene status and unfavourable cytogenetic aberrations in patients with chronic lymphocytic
leukaemia. Leukemia 18, 756–762 (2004).
34. Scielzo, C. et al. HS1 protein is differentially expressed in chronic lymphocytic leukemia patient subsets with
good or poor prognoses. J. Clin. Invest. 115, 1644–1650 (2005).
35. Rigolin, G. M. et al. Circulating endothelial cells in patients with chronic lymphocytic leukemia:
clinical-prognostic and biologic significance. Cancer 116, 1926–1937 (2010).
36. Bilban, M. et al. Deregulated expression of fat and muscle genes in B-cell chronic lymphocytic leukemia with
high lipoprotein lipase expression. Leukemia 20, 1080–1088 (2006).
37. Heintel, D. et al. High expression of lipoprotein lipase in poor risk B-cell chronic lymphocytic leukemia.
Leukemia 19, 1216–1223 (2005).
38. Oppezzo, P. et al. The LPL/ADAM29 expression ratio is a novel prognosis indicator in chronic lymphocytic
leukemia. Blood 106, 650–657 (2005).
39. Pallasch, C. P. et al. Overexpression of TOSO in CLL is triggered by B-cell receptor signaling and associated
with progressive disease. Blood 112, 4213–4219 (2008).
40. Kainz, B. et al. Overexpression of the paternally expressed gene 10 (PEG1O) from the imprinted locus on
chromosome 7q21 in high risk B-cell chronic lymphocytic leukemia. Int. J. Cancer 121, 1984–1993 (2007).
41. Buhl, A. M. et al. CLLU1 expression levels predict time to initiation of therapy and overall survival in chronic
lymphocytic leukemia. Eur. J. Haematol. 76, 455–464 (2006).
42. Josefsson, P. et al. CLLU1 expression analysis adds prognostic information to risk prediction in chronic
lymphocytic leukemia. Blood 109, 4973–4979 (2007).
43. Hewamana, S. et al. Rel a is an independent biomarker of clinical outcome in chronic lymphocytic leukemia. J.
Clin. Oncol. 27, 763–769 (2009).
44. Fayad, L. et al. Interleukin-6 and interleukin-10 levels in chronic lymphocytic leukemia: correlation with
phenotypic characteristics and outcome. Blood 97, 256–263 (2001).
45. Lai, R. et al. Prognostic value of plasma interleukin-6 levels in patients with chronic lymphocytic leukemia.
Cancer 95, 1071–1075 (2002).
46. Wierda, W. G. et al. Plasma interleukin 8 level predicts for survival in chronic lymphocytic leukemia. Br. J.
2
Haematol. 120, 452–456 (2003).
47. Molica, S. et al. Clinico-biological implications of increased serum levels of interleukin-8 in B-cell chronic
lymphocytic leukemia. Haematologica 84, 208–211 (1999).
48. Ferrajoli, A. et al. The clinical significance of tumor necrosis factor-alpha plasma level in patients having chronic
lymphocytic leukemia. Blood 100, 1215–1219 (2002).
49. Calin, G. A. et al. A MicroRNA signature associated with prognosis and progression in chronic lymphocytic
leukemia. N. Engl. J. Med. 353, 1793–1801 (2005).
50. Calin, G. A. & Croce, C. M. Chronic lymphocytic leukemia: interplay between noncoding RNAs and
protein-coding genes. Blood 114, 4761–4770 (2009).
51. Stamatopoulos, B. et al. MicroRNA-29c and microRNA-223 down-regulation has in vivo significance in chronic
lymphocytic leukemia and improves disease risk stratification. Blood 113, 5237–5245 (2009).
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