PMC

HOXA^Pos and HOXA^Neg adult T-ALL patients have similar survival outcomes. (A) Overall survival (OS) and (B) event-free survival (EFS) of HOXA^Pos and HOXA^Neg patients are shown. Five-year OS was estimated to be 55% (95% CI, 38.46% – 68.79%) in the HOXA^Pos group, as compared with 58.1% (95% CI, 48.50% – 66.49%) in HOXA^Neg cases. The corresponding figures for 5-year EFS were 45.9% (95% CI, 30.58% – 59.91%) for HOXA^Pos and 48.9% (95% CI, 39.73% – 57.53%) for HOXA^Neg.

An ETP-like immunophenotype is associated with an inferior prognosis in HOXA^Pos, but not HOXA^Neg adult T-ALL. The results of survival analyses after separation of the HOXA^Pos and HOXA^Neg groups according to the presence or absence of an ETP-like immunophenotype are shown. The 5-year survival figures were as follows: (A) overall survival (OS) for HOXA^Pos ETP 31.3% (95% CI, 11.4% – 53.7%), HOXA^Pos non-ETP 66.7% (95% CI, 42.5% – 82.5%), HOXA^Neg ETP 74.2% (95% CI, 45% – 89.4%), HOXA^Neg non-ETP 57.2% (95% CI, 46.1% – 66.9%). (B) Event-free survival (EFS) for HOXA^Pos ETP 25% (95% CI, 10.2% – 43.1%), HOXA^Pos non-ETP 52.7% (95% CI, 35.5% – 67.4%), HOXA^Neg ETP 60.8% (95% CI, 39.4% – 76.6%), HOXA^Neg non-ETP 50.7% (95% CI, 41.1% – 59.5%). (C) Disease-free survival (DFS) for HOXA^Pos ETP 28.6% (95% CI, 11.7% – 48.2%), HOXA^Pos non-ETP 53.6% (95% CI, 35.9% – 68.5%), HOXA^Neg ETP 64.7% (95% CI, 43.1% – 79.8%), HOXA^Neg non-ETP 52.2% (95%CI, 42.1% – 61.3%). (D) Cumulative incidence of relapse (CIR) for HOXA^Pos ETP 53.7% (95% CI, 34.3% – 75.6%), HOXA^Pos non-ETP 25.4% (95% CI, 13.6% – 44.4%), HOXA^Neg ETP 29.2% (95% CI, 15.1% – 51.6%), HOXA^Neg non-ETP 39.2% (95% CI, 30.6% – 49.3%).

Definition of HOXA^Pos adult T-ALL. (A) HOXA ratios (HOXA9/ABL) were calculated for 209 T-ALL patients treated as part of the GRAALL-2003 and -2005 studies. Each point represents an individual measurement. The threshold of HOXA positivity (0.66) was defined by the lowest HOXA ratio associated with a known HOXA-deregulating abnormality (PICALM-MLLT10). For HOXA^Pos cases for which the etiology of HOXA locus activation remained undefined, the measurement point is indicated by a diamond. Cases with an ETP-like phenotype are shown in red. (B) Taqman low density array (TLDA) analysis of HOX gene expression in HOXA^Neg (n = 8) and HOXA^Pos (n = 13) patients, compared with normal thymus (Thy) (n = 3) controls. HOXA^Pos cases exhibit specific activation of the HOXA locus, while HOXA^Neg samples have uniformly low expression of all HOX genes.

Molecular mechanism of HOXA deregulation in adult T-ALL. (A) Flowchart of investigation of the etiology of HOXA positivity. Numbers of patients in each diagnostic subgroup are shown.*One patient had co-existing diagnoses of both TCRβ-HOXA and PICALM-MLLT10. RNA-seq = RNA-sequencing. FISH = Fluorescence in situ hybridization. Representative results are depicted in panels (B) – (E). (B) Positive FISH for TCRβ-HOXA. (C) Direct (Sanger) sequencing confirms the presence of the NAP1L1-MLLT10 translocation. Exon numbers are indicated. (D) Reverse transcriptase polymerase chain reaction amplification of NUP98-RAP1GDS1 using fusion-specific primers. Patients 2 and 3 are positive for NUP98-RAP1GDS1, while patients 1 and 4 are negative. NTC = no template control. (E) Diagnosis of DDX3X-MLLT10 by RNA-sequencing. A schematic representation of paired-end and fusion-spanning reads is shown. Plain lines indicate split reads spanning two exons, and dotted lines indicate two reads of the same fragment. Exon numbers are indicated.