Prognostic and oncogenic relevance of TLX1/HOX11 expression level in T-ALLs

Abstract

TLX1 is a homeodomain transcription factor generally associated with a favorable outcome in T-cell acute lymphoblastic leukemia (T-ALL). However, the molecular mechanisms of TLX1 deregulation remain unclear and various transcript levels in the absence of 10q24 abnormalities have been reported. A reproducible and accurate delineation of TLX1 ؉ T-ALL will be necessary for proper therapeutic stratification. We have studied 264 unselected T-ALLs (171 adults and 93 children) and show that T-ALLs expressing high levels of TLX1 (n ‫؍‬ 35, 13%), defined as a realtime quantitative polymerase chain reaction (RQ-PCR) level of TLX1 greater than 1.00 ABL, form a homogeneous oncogenic group, based on their uniform stage of maturation arrest and oncogenetic and transcriptional profiles. Furthermore, TLX1-high T-ALLs harbor molecular TLX1 locus abnormalities in the majority (31/ 33), a proportion largely underestimated by standard karyotypic screening. TALLs expressing TLX1 at lower levels (n ‫؍‬ 57, 22%) do not share these characteristics. Prognostic analysis within the adult LALA94 and GRAALL03 prospective protocols demonstrate a better eventfree survival (P ‫؍‬ .035) and a marked trend for longer overall survival (P ‫؍‬ .059) for TLX1-high T-ALLs, while the expression of lower levels of TLX1 does not impact on prognosis. We propose that TLX1 ؉ T-ALLs be defined as cases expressing TLX1/ABL ratios greater than 1 and/or demonstrating TLX1 rearrangement. Therapeutic modification should be considered for those patients. (Blood. 2007; 110: [2324][2325][2326][2327][2328][2329][2330]

Oncogenetics and minimal residual disease are independent outcome predictors in adult patients with acute lymphoblastic leukemia

“…In T-ALL patients, variables that entered the prognostic analysis were as follows: WBC $100 3 10 9 /L, pro-T/mature-T phenotype, CNS involvement, complex karyotype, TLX1 gene overexpression defined as TLX1 over ABL expression ratio .1 as described previously, 27 highrisk genetic profile as defined above, and MRD1 level $10…”

TLX1-Induced T-cell Acute Lymphoblastic Leukemia

“…This TLX family member yields leukemias with a good prognostic outcome (1,2,10). After the discovery that TLX1 induces malfunction of the cellular mitotic checkpoint (16), it is tempting to speculate that this defective mitotic checkpoint in TLX1 tumors could indeed be related to increased sensitivity to chemotherapy drugs, inducing DNA damage and/or targeting the mitotic spindle.…”

“…Among T-ALL patients, TLX1-expressing tumors constitute a distinct molecular group, characterized by a block in T-cell differentiation at the early cortical stage of T-cell development (2) and by a favorable prognosis (1,2,10). Moreover, TLX1-induced leukemias represent a distinct oncogenic group with specific genetic alterations rarely found in non-TLX-induced T-ALLs, including the rearrangement of the NUP214-ABL1 oncogene (11), deletion of the PTPN2 phosphatase (12), and mutations in the WT1 (13) and PHF6 (14) tumor suppressor genes.…”

Gene expression profiling identifies a subset of adult T-cell acute lymphoblastic leukemia with myeloid-like gene features and over-expression of miR-223

“…2 The scenario is changing dramatically in this disease, since novel lesions are being ever more frequently recognized and will, most probably, allow therapeutic strategies to be tailored by targeting specific pathways. The most common aberrations include over-expression of TLX1 and TLX3 oncogenes; [3][4][5] both transcripts have prognostic significance, with TLX1 being associated with a favorable outcome 6,7 and TLX3 with a worse outcome, [8][9][10] although some exceptions have been reported. 11,12 The most frequent of the recognized mutations is NOTCH1, 13 found in roughly 50% of cases of T-ALL and generally associated with other aberrations, including FBXW7 (detected in 8-16% of cases).…”