Leukemia takes center (late) stage

In this issue of Blood,Newrzela and colleagues present experiments that show how mature Tlymphocytes are resistant to transformation by retrovirally transduced T-cell oncogenes.

Retroviral transduction of hematopoietic stem cells and progenitors is used to evaluate the function of putative oncogenes and is a common way to deliver therapeutic transgenes. Constitutive expression of an oncogene activated by nearby insertion of a retroviral promoter can result in a phenotype similar to sporadically occurring gain-of-function mutations in the same oncogene. Likewise, retroviral integration near an oncogene can deregulate its expression, mimicking chromosomal rearrangements that exert the same effect in sporadically occurring leukemias. In such experiments testing oncogene function, the preferred target cell for retroviral transduction is the hematopoietic stem cell (HSC) because it gives long-term reconstitution of hematopoiesis in lethally irradiated hosts and is capable of self-renewal, an important hallmark of cancer. Lymphocytes are unique among hematopoietic lineages in that they also can self-renew.¹  Then, does it follow that mature T cells are as susceptible to oncogenic transformation as HSCs?

Newrzela et al address this question through retroviral delivery of 3 potent oncogenes, LIM domain Only-2 (LMO2), T-cell Leukemia-1 (TCL1), and Δ-TrkA. LMO2 is translocated to T-cell receptor loci in 5% to10% of T-cell acute lymphoblastic leukemias (T-ALL).²  Typically, these leukemias arise from immature T cells in the thymus. LMO2 was also deregulated in 4 cases of gene therapy induced leukemias where the gamma-retroviral vector insertionally activated the oncogene. TCL1 deregulation was also originally discovered through analysis of a recurrent chromosomal translocation in a mature T-cell leukemia.³  Δ-TrkA was cloned from a human acute myeloid leukemia.⁴  This truncated and constitutively active form of TrkA gives rise to myeloid and immature T-cell leukemias when retrovirally transduced into HSCs.⁵  In the experiments detailed in the paper by Newrzela et al, these 3 oncogenes were retrovirally transduced in HSCs and mature T cells, and the cells were subsequently transplanted into irradiated hosts. The researchers attained high-level expression of the transferred genes in both target cell populations, and transduced cells could be followed by unique cell surface markers in RAG-deficient recipient mice.

The 3 oncogenes induced leukemias in recipients of transduced HSCs, but the recipients of transduced mature T cells did not develop disease. Transduced lymphocytes were transplanted again into secondary irradiated recipients and no leukemia was seen, even though there was high-level expression of the transgenes and prolonged in vivo observation, up to 1 year in some serial transplant experiments. Integration site analysis did not show clonal selection that would suggest preleukemic hyperplasia in the secondary transplanted mature T cells. Too few retroviral insertions were cloned for comparison of HSCs versus mature T-cell integration patterns.

The authors conclude that mature T cells are resistant to oncogenic transformation. However, another interpretation for these results is that the tested oncogenes, particularly LMO2 and Δ-TrkA, are active in a developmental stage–specific manner. For example, the LMO2 oncogene is frequently coexpressed in T-ALLs with class II basic HLH proteins, such as TAL1 with which it forms oligomeric complexes.²  Whereas TAL1 expression is seen in HSCs and immature T cells, the gene is not expressed in mature T cells. This explanation is less applicable to TCL1, which causes mature T- cell prolymphocytic leukemias. Alternatively, HSCs may be more prone to accumulating cooperating mutations than mature T cells, perhaps due to increased sensitivity to replicative stress. In future studies, the retroviral transduction and transplantation of HSCs and mature T cells should be tried with a larger panel of oncogenes to test these possibilities.