Age-related phenotypic and oncogenic differences in T-cell acute lymphoblastic leukemias may reflect thymic atrophy

Abstract

Postnatal thymic involution occurs progressively throughout the first 3 decades of life. It predominantly affects T-cell receptor (TCR) ␣␤-lineage precursors, with a consequent proportional increase in multipotent thymic precursors. We show that T-acute lymphoblastic leukemias (TALLs) demonstrate a similar shift with age from predominantly TCR expressing to an immature (IM0/␦/␥) stage of maturation arrest. Half demonstrate HOX11, HOX11L2, SIL-TAL1, or CALM-AF10 deregulation, with each being associated with a specific, age-independent stage of maturation arrest. HOX11 and SIL-TAL represent ␣␤-lineage oncogenes, whereas HOX11L2 expression identifies an intermediate ␣␤/␥␦-lineage stage of maturation arrest. In keeping with preferential ␣␤-lineage involution, the incidence of SIL-TAL1 and HOX11L2 deregulation decreased with age. In contrast, HOX11 deregulation became more frequent, suggesting longer latency. TAL1/LMO1 deregulation is more frequent in ␣␤-lineage T-ALL, when it is predominantly due to SIL-TAL1 rearrangements in children but to currently unknown mechanisms in adolescents and adults. LMO2 was more frequently coexpressed with LYL1, predominantly in IM0/␦/␥ adult cases, than with TAL1. These age-related changes in phenotype and oncogenic pathways probably reflect progressive changes in the thymic population at risk of malignant transformation. ( IntroductionHuman T lymphocytes are derived from pluripotent hemopoietic progenitors that migrate throughout life from the bone marrow to the thymus, where the majority of T-cell development occurs. Progressive thymic atrophy during the first 2 to 3 decades of life leads to a reduction of thymic mass and, to a lesser extent, function. 1,2 The earliest thymic progenitor corresponds to a minor (Ͻ 1% of thymocytes) sCD3 Ϫ , CD4/CD8 double-negative (DN) population that does not alter with age. [3][4][5][6] In the neonatal murine thymus, the majority of lymphocytes belong to the ␣␤ lineage; successful T-cell receptor ␤ (TCR␤) rearrangement in a DN precursor in the presence of pT␣ allows expression of the pre-TCR in association with CD3, progression to the CD4/8 double-positive (DP) stage, and massive thymocyte expansion, a process known as ␤ selection 7 ; this population diminishes markedly with age, with a consequent increase in the proportion of DN cells.T-acute lymphoblastic leukemias (T-ALLs) correspond to a heterogeneous group of acute leukemias arrested at various stages of lymphoid development. They account for 10% to 15% of pediatric and 25% of adult ALLs, with a relatively constant incidence up to the third decade. [8][9][10] Recognized T-ALL oncogenic pathways include transcriptional deregulation by juxtapositioning to one of the TCR loci, resulting in transcriptional deregulation of genes such as HOX11/TLX1, LMO2, LMO1, LYL1, and TAL1/SCL, each of which is present in less than 10% of cases. [11][12][13][14][15][16][17][18][19][20][21][22] More common genetic defects in T-ALL are submicroscopic deletions of p16/INK4 in 40% to 80% 23,24 or SIL-TAL1 in 10% to ...

Dysregulated expression of mitotic regulators is associated with B-cell lymphomagenesis in HOX11-transgenic mice

“…However, another implication of this disease mechanism is the expectation that HOX11 þ cancers would be especially sensitive to high doses of spindle poisons, which should promote catastrophic chromosomal abnormalities and induce cell death. Indeed, relative to other T-ALL subtypes, HOX11 þ T-ALLs have been demonstrated to be exceedingly responsive to combination chemotherapies (Asnafi et al, 2004;Ferrando et al, 2004), which typically employ spindle poisons in the treatment regimen. It may also explain the refractory nature of relapsed HOX11 þ T-ALLs to chemotherapy, which likely possess a complex karyotype, and the resultant need for bone marrow transplantation therapy for second-line treatment (Asnafi et al, 2005).…”

“…Clinically, patients with HOX11-positive lymphoblasts have a better prognosis when treated with modern combination chemotherapy than patients with T-ALLs involving activation of HOX11L2 (Ferrando et al, 2002(Ferrando et al, , 2004. The incidence of HOX11-positive lymphomas correlates with increasing age, indicating a longer latency for disease manifestation and suggesting the requirement of additional genetic events prior to malignancy (Asnafi et al, 2004).…”

Thymic adult T-cell acute lymphoblastic leukemia stratified in standard- and high-risk group by aberrant HOX11L2 expression: experience of the German multicenter ALL study group

“…Also, little is known about a correlation of molecular data and the immunologic subtypes as an already established prognostic factor. 9 Thus, we have retrospectively evaluated the incidence and prognostic impact of HOX11 and HOX11L2 expression in 286 immunologically well-characterized adult T-ALL patients.…”

“…6 However, available data are controversial regarding the clinical impact of aberrant HOX11 and HOX11L2 expression in childhood T-ALL, and few data are available in adult patients. [7][8][9][10] The pediatric and adult population might differ substantially in the activation status of these oncogenes. Also, little is known about a correlation of molecular data and the immunologic subtypes as an already established prognostic factor.…”

Mécanisme d’action des oncogènes à homéodomaine TLX dans les LAL-T

“…Un métabolisme primitif nécessite égale-ment que ces polymères soient capables de se replier dans des structures tertiaires stables ayant des fonctionnalités élaborées telles que la reconnaissance d'un ligand et la catalyse [5]. Parmi les systèmes étudiés, l'acide nucléique (3', 2')--L-thréose (ANT, Figure 1) pourrait jouer le rôle de précur-seur de l'ARN en raison de sa simplicité structurale -son squelette est constitué de thréoses qui ont un carbone de moins que les riboses de l'ARN -et de sa capacité à former des structures hélicoïdales stables avec des brins complémentaires d'ANT ou d'ARN [6][7][8].…”