The phosphoinositide 3-kinase pathway in chronic lymphocytic leukemia

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E-mail: [email protected] This commentary accompanies an article to be published in Leukemia & Lymphoma. Please refer to the table of contents of the ...

Leukemia & Lymphoma, June 2013; 54(6): 1123–1124 © 2013 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2012.746685

COMMENTARY

The phosphoinositide 3-kinase pathway in chronic lymphocytic leukemia: evidence for phosphatase and tensin homolog deletion on chromosome 10 deregulation O. Giles Best & Stephen P. Mulligan

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Northern Blood Research Centre, Kolling Institute, Royal North Shore Hospital, Sydney, Australia

The phosphoinositide 3-kinase (PI3-kinase) signaling pathway plays a pivotal role in cellular growth, survival, motility and proliferation. As many of these functions underlie tumorigenesis, metastasis and drug resistance, it is not surprising that the PI3-kinase pathway has been identified as one of the most commonly deregulated in human cancers and is considered a highly relevant therapeutic target. PI3-kinase activation by extracellular stimuli, such as growth factors and cytokines, results in the phosphorylation of phosphoinositides (PIPs), which recruit downstream effector molecules to the inner surface of the plasma membrane. The PIP phosphoinositol-3,4,5triphosphate (PIP3) specifically binds and activates the kinase PDK1, which in turn phosphorylates PIP3-bound Akt. Akt promotes cell survival by direct inhibition of proteins such as BAD and I-kappa kinase (IKK) and through transcriptional regulation of a panel of genes that confer resistance to apoptosis and promote proliferation. Tight regulation of Akt activity is therefore key in preventing malignant transformation, and is in part achieved through the dephosphorylation of PIP3 by PTEN (phosphatase and tensin homolog deleted on chromosome 10). Given the high incidence of cancers with mutations or low expression of PTEN, including malignancies of the prostate, breast and colon, PTEN is classified as a tumor suppressor (for recent review see [1]). Leukemogenesis and cell proliferation in chronic lymphocytic leukemia (CLL) relies on sustained activation of anti-apoptotic/pro-survival pathways [2]. In CLL cells the PI3-kinase/Akt pathway has been well documented as playing a critical role in cell survival. However, there is limited evidence in the literature to suggest that deregulation of PTEN contributes to the constitutive activity of Akt observed in CLL cells. The study by Zou and colleagues published in this issue of Leukemia and Lymphoma is the first to suggest that levels of PTEN transcript correlate with well-documented indicators of poor prognosis in CLL [3]. The study demonstrated that PTEN mRNA

expression was significantly lower within samples from a cohort of 103 patients with CLL than in 20 samples from age-matched healthy donors, and that expression was lower among samples from patients with advanced stage disease, unmutated IgVH genes, unfavorable cytogenetic lesions or high β2-microglobulin, lactate dehydrogenase or ZAP-70 expression. Furthermore, the study demonstrated that low PTEN levels were associated with a shorter time to first treatment. Loss of heterozygosity (LOH) of the PTEN genetic locus, 10q23.3, occurs in approximately 20% of cases of CLL [4]. This was confirmed in a study by Leupin et al., in which LOH or genomic imbalance at 10q23.3 was identified in 8/41 (20%) patients, but in none of the cases were these lesions found to encompass the PTEN gene or were mutations of the PTEN gene identified [5]. Despite the apparent integrity of the PTEN gene, Leupin et al. noted that expression of PTEN protein was low or absent in 19/41 (46%) cases. Taken together, the findings of Zou et al. and Leupin et al. strongly suggest that PTEN mRNA and protein levels are low or indeed absent in a significant number of CLL patient samples, implying that epigenetic silencing, probably as a result of promoter methylation or miRNA interference [6] rather than increased protein degredation, may account for the low levels of PTEN observed in both studies. Combined with the possibility that post-translational modification of the PTEN protein may also occur in CLL cells, as in other cancers [7], it is increasingly likely that a significant proportion of patients with CLL exhibit some degree of PTEN inactivation and that this contributes to the constitutive activity of the PI3-kinase/Akt pathway in CLL cells. The PI3-kinase/Akt pathway represents a very promising target for therapy in CLL, as clinical trials of the PI3-kinase δ-isoform inhibitor GS-1101 (formerly known as CAL-101) are proving [8]. Deregulation of PTEN appears to represent a further mechanism which drives signaling through this pathway, and provides further rationale for targeting this pathway in CLL.

Correspondence: Dr. Giles Best, Northern Blood Research Centre, Kolling Institute, Royal North Shore Hospital, St Leonards, Sydney, NSW 2065, Australia. Tel: ⫹ 61(0)99264860. Fax: ⫹ 61(0)99265716. E-mail: [email protected] This commentary accompanies an article to be published in Leukemia & Lymphoma. Please refer to the table of contents of the print issue in which this commentary appears.

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Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.

References

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[1] Song MS, Salmena L, Pandolfi PP. The functions and regulation of the PTEN tumour suppressor. Nat Rev Mol Cell Biol 2012;13:283–296. [2] Wickremasinghe RG, Prentice AG, Steele AJ. Aberrantly activated anti-apoptotic signalling mechanisms in chronic lymphocytic leukaemia cells: clues to the identification of novel therapeutic targets. Br J Haematol 2011;153:545–556. [3] Zou ZJ, Zhang R, Fan L, et al. Low expression level of phosphatase and tensin homolog deleted on chromosome ten predicts poor prognosis in chronic lymphocytic leukemia. Leuk Lymphoma 2013;54:1159–1164.

[4] Novak U, Oppliger Leibundgut E, Hager J, et al. A high-resolution allelotype of B-cell chronic lymphocytic leukemia (B-CLL). Blood 2002;100:1787–1794. [5] Leupin N, Cenni B, Novak U, et al. Disparate expression of the PTEN gene: a novel finding in B-cell chronic lymphocytic leukaemia (B-CLL). Br J Haematol 2003;121:97–100. [6] Yamanaka Y, Tagawa H, Takahashi N, et al. Aberrant overexpression of microRNAs activate AKT signaling via down-regulation of tumor suppressors in natural killer-cell lymphoma/leukemia. Blood 2009;114:3265–3275. [7] Ross AH, Gericke A . Phosphorylation keeps PTEN phosphatase closed for business. Proc Natl Acad Sci USA 2009; 106:1297–1298. [8] Furman RR, Byrd JC, Brown JR, et al. CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3-kinase P110{delta}, demonstrates clinical activity and pharmacodynamic effects in patients with relapsed or refractory chronic lymphocytic leukemia. Blood 2010;116(Suppl. 1): Abstract 55.