Immunobiological diversity in infant acute lymphoblastic leukemia is related to the occurrence and type of MLL gene rearrangement

Abstract

The aim of this study was to identify immunobiological subgroups in 133 infant acute lymphoblastic leukemia (ALL) cases as assessed by their immunophenotype, immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangement pattern, and the presence of mixed lineage leukemia (MLL) rearrangements. About 70% of cases showed the pro-B-ALL immunophenotype, whereas the remaining cases were common ALL and pre-B-ALL. MLL translocations were found in 79% of infants, involving MLL-AF4 (41%), MLL-ENL (18%), MLL-AF9 (11%) or another MLL partner gene (10%). Detailed analysis of Ig/TCR rearrangement patterns revealed IGH, IGK and IGL rearrangements in 91, 21 and 13% of infants, respectively. Cross-lineage TCRD, TCRG and TCRB rearrangements were found in 46, 17 and 10% of cases, respectively. As compared to childhood precursor-B-ALL, Ig/TCR rearrangements in infant ALL were less frequent and more oligoclonal. MLL-AF4 and MLL-ENL-positive infants demonstrated immature rearrangements, whereas in MLL-AF9-positive leukemias more mature rearrangements predominated. The immature Ig/TCR pattern in infant ALL correlated with young age at diagnosis, CD10 negativity and predominantly with the presence and the type of MLL translocation. The high frequency of immature and oligoclonal Ig/TCR rearrangements is probably caused by early (prenatal) oncogenic transformation in immature B-lineage progenitor cells with germline Ig/TCR genes combined with a short latency period.

Lineage switch in childhood acute leukemia: An unusual event with poor outcome

“…In Case 6, a Vh replacement in a complete Vh-Dh-Jh complex was detected, corresponding to a secondary rearrangement. The absence of Ig or TCR in Case 8 and the detection of only an IGH rearrangement in Case 9, both MLL positive leukemias, could be related to the association of MLL with a more immature pattern [28].…”

Detection of fusion genes at the protein level in leukemia patients via the flow cytometric immunobead assay

“…Thus far, at least 64 different MLL partner genes have been identified in acute leukemia patients [33,34]. Despite this exceptionally high number of different partner genes, only six different partner genes are found in w85% of acute leukemias with an MLL fusion gene: AF4, AF9, ENL, AF10, AF6 and ELL [34].…”

“…This multiplex immunobead assay can detect in a single step the most frequently occurring MLL fusion proteins in MLL þ acute leukemias. (Table 3) [33,34]. Also, the prognosis of these MLL gene aberrations ranges from mainly poor for most MLL gene aberrations to fairly good for, for instance, MLL-AF9 in AML.…”

Age-related differences in leukemia biology and prognosis: the paradigm of MLL-AF4-positive acute lymphoblastic leukemia

“…Two studies reported in this issue of Leukemia demonstrate a high prevalence of immature, nonproductive and/or oligoclonal antigen-receptor gene rearrangements in infant ALL with MLL fusions. 8,10 Overall, infant leukemias had gene rearrangement patterns that were different from those of leukemias diagnosed in older children (including those with MLL fusions), 8,10 suggesting that infant cases originated mostly from a lymphoid progenitor with germline or incompletely rearranged antigen-receptor genes. 8,10 Leukemogenic events during fetal development may also result in distinct MLL breakpoints.…”

“…8,10 Overall, infant leukemias had gene rearrangement patterns that were different from those of leukemias diagnosed in older children (including those with MLL fusions), 8,10 suggesting that infant cases originated mostly from a lymphoid progenitor with germline or incompletely rearranged antigen-receptor genes. 8,10 Leukemogenic events during fetal development may also result in distinct MLL breakpoints. Thus, Reichel et al 11 found that 13 of 24 infants less than 1 year of age had breakpoints in the telomeric part of the MLL breakpoint cluster region, whereas 29 of 34 children and adults had breakpoints in the centromeric part of the MLL breakpoint cluster region.…”