cell cycle features
cell cycle features
Cell Cycle 9:12, 2267-2268; June 15, 2010; © 2010 Landes Bioscience
The thymus under siege
Lmo2 induces precancerous stem cells in a mouse model of T-ALL Matthew P. McCormack* and David J. Curtis The Rotary Bone Marrow Research Laboratories; Royal Melbourne Hospital; Parkville, VIC Australia; and Department of Medicine; University of Melbourne; Parkville, VIC Australia
Key words: LMO2, thymus, leukemia, self-renewal, cancer stem cells Abbreviations: T-ALL, T-cell acute lymphoblastic leukemia; HSC, hematopoietic stem cell; pre-CSC, precancerous stem cell; CSC, cancer stem cell; bHLH, basic helix-loop-helix; LMO, lim-domain only T-cell acute lymphoblastic leukemia (T-ALL) is a predominantly pediatric leukemia, the cell-of-origin of which has remained obscure. We have recently described a population of self-renewing cells in a mouse model of T-ALL, which can be detected in the thymus many months prior to the generation of leukemia.1 The presence of these cells was most clearly demonstrated using a lineage tracing system in which hematopoietic stem cells (HSCs) are inducibly marked with YFP, allowing us to track thymic turnover from the bone marrow. Unlike the thymus of normal mice, which is continually replenished by progenitors from the bone marrow, the thymus of Lmo2transgenic mice was self-sustaining from a young age. This suggested that the thymi of Lmo2-transgenic mice contain cells with self-renewal capacity, unlike the normal thymus that has no self-renewal potential. These cells were then definitively isolated using serial transplantation assays. As these thymus-maintaining cells have stem cell like properties but do not cause overt leukemia for many months, we refer to them as precancerous stem cells (pre-CSCs) (Fig. 1). These findings are consistent with the ability to detect chromosomal translocations in humans long prior to leukemia and even in utero.2 Our findings have strong parallels with both acute myeloid leukemia (AML) and common (B-cell) ALL, both of which can
be caused by aberrant self-renewal of committed progenitors due to transcription factor overexpression.3,4 Most T-ALL cases feature the overexpression of oncogenic transcription factors, either through chromosomal abnormalities or other unknown mechanisms. Commonly activated transcription factors include the basic helix-loop-helix (bHLH) genes TAL1, TAL2 and LYL1, the Lim-domain only (LMO) genes LMO1 and LMO2 and the homeobox transcription factors HOX11 and HOX11L2.5 Most of these genes are not required for normal T-cell development suggesting that it is their overexpression that causes T-ALL. In addition to its role in spontaneous T-ALL, overexpression of LMO2 due to retroviral insertion mutagenesis was the cause of 4 cases of T-ALL following gene therapy for the disease X-linked severe combined immunodeficiency (X-SCID).6-8 As the bHLH and LMO proteins interact to form transcriptional complexes it is likely that they function via a similar or shared mechanism. Until recently, this mechanism was thought to involve the inhibition of T-cell developmental genes due to blocking E protein function.9 However, our study revealed that Lmo2 also activates the expression of several HSCassociated genes in developing T-cells in the thymus. One of the most upregulated genes in Lmo2-overexpressing thymocytes was the hematopoietically-expressed
homeobox (Hhex) gene, which is a close relative of the T-cell oncogene Hox11. To test whether Hhex overexpression is sufficient for thymocyte self-renewal, we retrovirally expressed Hhex in the thymus. Surprisingly, this generated self-renewing thymocytes in vivo that bore striking resemblance to those found in Lmo2transgenic thymi. Hence Hhex overexpression may be a key component of the Lmo2-induced self-renewal programme. These findings are interesting given that homeobox genes are key components of the normal HSC self-renewal program, and are associated not only with Hox11associated T-ALL, but also with myeloid leukemia driven by oncogenes such as MLL fusion proteins.10 Self-renewal mediated by homeobox transcription factors may therefore be a widespread mechanism underpinning leukemia. A second major finding of our study was that Lmo2-induced pre-CSCs are remarkably resistant to conventional therapies. Indeed, when high-dose radiotherapy was used, over 99% of thymus cells were eliminated, but Lmo2-induced preCSCs could persist and rapidly recover. This suggests that pre-CSCs may survive conventional therapy and give rise to relapse. This is in accordance with a recent study demonstrating that in the majority of cases, relapsed ALL consists of a different clonal population from that present at initial diagnosis.11 This suggests that the
*Correspondence to: Matthew P. McCormack; Email:
[email protected] Submitted: 04/14/10; Accepted: 04/14/10 Previously published online: www.landesbioscience.com/journals/cc/article/12074 Comment on: McCormack MP, et al. Science 2010; 327:879–83. www.landesbioscience.com
Cell Cycle
2267
Figure 1. Precancerous stem cells (pre-CSCs) versus cancer stem cells (CSCs) in leukemia. Self-renewal (curved arrow) is normally restricted to hematopoietic stem cells (HSCs). Initiating oncogenic events, such as activation of Lmo2, can induce self-renewal of committed progenitors, producing pre-CSCs. Further mutations cause evolution of these cells into CSCs that cause overt leukemia.
cells responsible for relapse are ancestral to the primary leukemia cells, and that relapsed disease may in fact derive from pre-CSCs rather than CSCs (Fig. 1). For this reason it is critical to find therapies that can eliminate pre-CSCs to prevent leukemia relapse. Lmo2 transgenic mice may be a useful model for the identification and testing of such therapies.
2268
References 1. 2.
McCormack MP, et al. Science 2010; 327:879-83. Greaves MF, Wiemels J. Nat Rev Cancer 2003; 3:63949. 3. Huntly BJ, Gilliland DG. Nat Rev Cancer 2005; 5:311-21. 4. Hong D, et al. Science 2008; 319:336-9. 5. Aifantis I, et al. Nat Rev Immunol 2008; 8:380-90.
Cell Cycle
6.
McCormack MP, Rabbitts TH. N Engl J Med 2004; 350:913-22. 7. Howe SJ, et al. J Clin Invest 2008; 118:3143-50. 8. Hacein-Bey-Abina S, et al. J Clin Invest 2008; 118:3132-42. 9. O’Neil J, et al. Cancer Cell 2004; 5:587-96. 10. Argiropoulos B, Humphries RK. Oncogene 2007; 26:6766-76. 11. Mullighan CG, et al. Science 2008; 322:1377-80.
Volume 9 Issue 12
