Prognostic Impact of the Expression of the TLX1 (HOX11) and TLX3 (HOX11L2) Oncogenes in Adult ALL: Experience of the German Multicenter Acute Lymphoblastic Leukemia (GMALL) Therapy Study Group.

Background: Controversial data exist concerning the prognostic impact of the expression of the two orphan HOX genes TLX1 and TLX3 in pediatric and adult ALL. To further clarify this situation we have investigated adult T-ALL patients for the expression of the TLX1 and TLX3 oncogenes using Real Time quantitative PCR. Altogether 146 cases of adult T-lineage ALL, treated according to the German Multicenter ALL (GMALL) Therapy trial 5/93, were investigated, thus, representing the largest cohort of adult T-ALL patients investigated so far.

Methods: Analysis was done with a Rotor Gene 3000 cycler. PCR primers and TaqMan probes were located in exon 1 and exon 2 of TLX1 and in exon 5 and 6 of TLX3. Cell lines HPB-ALL and ALL-SIL were used as positive controls and samples of healthy donors were used as negative controls.

Patients: The mean age of the patients was 31 (16–63) ys. Thirty-seven patients (25.2%) had an early T-ALL, 33 (22.5%) had a thymic T-ALL and 77 (52.4%) had a mature T-ALL.

Results: Fourty-six patients (43%) were TLX1-positive, 15 (10%) were TLX3-positive and 6 (4.1%) showed an expression of both oncogenes. The TLX1-expression was significantly associated with the immunophenotype: 19% (7/36) of early T, 18% (6/33) of mature T and 43% (33/77) of thymic T-ALL were TLX1-positive (p=0.0077). There was no significant association of the TLX3-positive cases with a certain immunophenotype: (8 (10%) thymic, 2 (6%) mature, 5 (14%) early) (p>.05). There were no significant differences in CR rates between the TLX1- and TLX3-positive patients. The probabilities of survival in the 4 different subgroups were as follows: TLX1-positive/TLX3-negative 0.57 (N=40), TLX1-negative/TLX3-negative 0.37 (N=91), TLX1-negative/TLX3-positive 0.20 (N=9), TLX1-positive/TLX3-positive 0.00 (N=6) (p log rank = 0.01). The probabilities of continuous complete remission (CCR) in the 4 subgroups (129 eligible patients) were the following:

TLX1-positive/TLX3-negative 0.71 (N=36), TLX1-negative/TLX3-negative 0.45 (N=80), TLX1-negative/TLX3-positive 0.20 (N=9), TLX1-positive/TLX3-positive 0.0 (N=4) (p log rank = 0.04). Within the three different immunophenotypic subgroups the expression of TLX1/TLX3 did not show a significant association with survival or CCR.

Conclusions: The GMALL study group has shown previously that the immunologic subtypes of T-ALL are significantly associated with outcome, with poorer survival for early/mature T-ALL and better outcome for thymic T-ALL. The data presented here show that TLX1 expression is associated with a favourable immunophenotype and a better prognosis. TLX3 expression is not significantly associated with certain immunophenotypes and confers an inferior outcome both in remission duration and overall survival in adult ALL. The patients disclosing expression of both oncogenes showed the worst prognosis but comprised only a small number (6/147). These results suggest that TLX3-positive patients, particularly those with coexpression of TLX1, should be treated as a high risk group.