Gene expression profiles predictive of outcome and age in infant acute lymphoblastic leukemia: a Children's Oncology Group study

Abstract

Gene expression profiling was performed on 97 cases of infant ALL from Children's Oncology Group Trial P9407. Statistical modeling of an outcome predictor revealed 3 genes highly predictive of eventfree survival (EFS), beyond age and MLL status: FLT3, IRX2, and TACC2. Low FLT3 expression was found in a group of infants with excellent outcome (n ‫؍‬ 11; 5-year EFS of 100%), whereas differential expression of IRX2 and TACC2 partitioned the remaining infants into 2 groups with significantly different survivals (5-year EFS of 16% vs 64%; P < .001). When infants with MLL-AFF1 were analyzed separately, a 7-gene classifier was developed that split them into 2 distinct groups with significantly different outcomes (5-year EFS of 20% vs 65%; P < .001). In this classifier, elevated expression of NEGR1 was associated with better EFS, whereas IRX2, EPS8, and TPD52 expression were correlated with worse outcome. This classifier also predicted EFS in an independent infant ALL cohort from the Interfant-99 trial. When evaluating expression profiles as a continuous variable relative to patient age, we further identified striking differences in profiles in infants less than or equal to 90 days of age and those more than 90 days of age. These age-related patterns suggest different mechanisms of leukemogenesis and may underlie the differential outcomes historically seen in these age groups. (Blood. 2012; 119(8):1872-1881)

Tumor protein D52 represents a negative regulator of ATM protein levels

“…45 However, these mechanisms could only occur in a small proportion of breast cancers, whereas downregulation of ATM is observed in up to 75% cases. 39 Interestingly, increased TPD52 expression has been identified in many different types of cancer, including breast cancer, [46][47][48] colorectal cancer, 49 leukemia, and lymphoma, [50][51][52] which overlap with the spectrum of ATM-deficient malignancies. It is of particular interest that increased TPD52 expression has been associated with radiosensitivity in independent studies using lymphocytes or lymphoblastoid cell lines, 23,24 indicating that variations in TPD52 levels could alter radiosensitivity in normal cells.…”

Pediatric acute lymphoblastic leukemia: where are we going and how do we get there?

“…48 The association of high expression of FLT3 with a poor outcome in infant ALL cases without MLL rearrangement suggests that these infants could also be included in clinical trials testing an FLT3 inhibitor. 49 It may also be of interest to test the multikinase inhibitors sorafenib and crenolanib, which have significant activity in acute myeloid leukemia with mutated FLT3, 50 in infant cases. The findings of aberrant DNA methylation in the majority of MLL-rearranged infant ALL cases 51,52 and mutations of CREBBP encoding histone acetyltransferase CREB-binding protein in relapsed ALL cases 45 raise the possibility of using epigenetic PEDIATRIC ACUTE LYMPHOBLASTIC LEUKEMIA 1167 BLOOD, 9 AUGUST 2012 ⅐ VOLUME 120, NUMBER 6…”

HLA DRB1*, DQB1*, DPA1*, and DPB1* and their association with the pathogenesis of leukemia in the population of Venezuela

“…20 Una fuerte asociación HLA-DQB1*0201, -DQB1*0302, -DQB1*0303 y -DRB1*1302 fue reportada en 824 casos de pacientes LLA-BCP confrontados con 4.737 controles en la población del Reino Unido. 21,22 En pacientes mexicanos los alelos HLA DRB1*01:02, DQB1*02:01/02 y DPB1*04:01 resultaron protectores para la LLA, el alelo DQB1*02 resultó protector también para las LMC en venezolanos. DQB1*03:01 y DPB1*04:02 se reportaron como de riesgo para las LLA en dicha población mexicana.…”