Mixed Lineage Leukemia–Rearranged Childhood Pro-B and CD10-Negative Pre-B Acute Lymphoblastic Leukemia Constitute a Distinct Clinical Entity

Abstract

Purpose: Mixed lineage leukemia (MLL) abnormalities occur in f50% of childhood pro-B acute lymphoblastic leukemia (ALL). However, the incidence and type of MLL rearrangements have not been determined in common ALL (cALL) and CD10+ or CD10À pre-B ALL. Experimental Design: To address this question, we analyzed 29 patients with pro-B ALL, 11patients with CD10À pre-B ALL, 23 pre-B, and 26 cALL patients with CD10 on 20% to 80%, as well as 136 pre-B and 143 cALL patients with CD10 z80% of blasts. They were all enrolled in four Austrian ALL multicenter trials. Conventional cytogenetics were done to detect 11q23 abnormalities and in parallel the potential involvement of the MLL gene was evaluated with a split apart fluorescence in situ hybridization probe set. Results:We found that15 of 29 pro-B ALL, 7 of11CD10À pre-B ALL, and1of 2 French-AmericanBritish classification L1 mature B-cell leukemia cases had a MLL rearrangement. However, no 11q23/MLL translocation was identified among the CD10+ pre-B and cALL patients. MLL-rearranged pro-B and CD10À pre-B ALL cases had similar clinical and immunophenotypic (coexpression of CDw65 and CD15) features at initial diagnosis. Conclusions: The striking similarities between the two CD10À ALL subsets imply that CD10À pre-B ALL variants may represent pro-B ALL cases that maintained the propensity to rearrange and express their immunoglobulin heavy chain rather than actual pre-B ALL forms transformed at this later stage of B-cell differentiation. However, direct experimental data are needed to confirm this observation.Rearrangements involving the mixed lineage leukemia (MLL) gene on chromosome band 11q23 represent nonrandom chromosomal abnormalities commonly found in human hematologic malignancies, including both acute lymphoblastic leukemia (ALL; 5-10%) and acute myeloid leukemia (AML; 5%; refs. 1, 2). Although the exact function of the MLL gene is unclear, it displays intrinsic histone methyltransferase activity and is known to play an important role in maintaining a cell type -specific expression of HOX genes, which are necessary for the cellular differentiation process (2, 3).According to most published series, MLL-rearranged B-cell precursor (BCP) ALL can be reliably identified by a distinct immature CD10À/CD24À phenotype that is commonly characterized by the concurrent expression of the myeloid markers CDw65 and CD15, and of the chondroitin sulfate proteoglycan neuron-glial antigen 2 (NG2; refs. 4 -7). Due to the observation that the translocation t(4;11) with its molecular counterpart, the MLL/AF4 fusion gene, is the most frequent MLL-specific aberration in infants with pro-B ALL, the CD10 negativity of MLL-rearranged BCP leukemia is commonly regarded as a sign of cellular immaturity (2,8,9). Furthermore, the coexpression of CDw65 and CD15 is taken as an evidence that this type of leukemia even represents a transformed upstream lymphomyelomonocytic progenitor cell.As recent collaborative studies showed a marked clinical heterogeneity among MLL-rearranged ALL requiring d...

Validation of NG2 antigen in identifying BP-ALL patients with MLL rearrangements using qualitative and quantitative flow cytometry: a prospective study

“…Furthermore, in 2 out of 30 MLL-positive cases analyzed by GS methods, the rearrangement was found in CD10( þ ) samples: one in a patient with CALL and one in a patient with pre-B ALL. While Attarbaschi et al 8 question the use of NG2 as a marker for MLL rearranged BPC-ALL, we point out that NG2 expression, evaluated by a combination of qualitative and quantitative FC analysis, is a highly reliable marker for MLL diagnosis, more than the absence of CD10. By collecting immunophenotypic NG2 data from 1461 B-ALL patients using both qualitative and quantitative methods, we tested FC performances according to GS response: sensitivity, specificity, predictive values and accuracy for both approaches produced comparable results with no significant differences in MLL diagnosis.…”

“…2,[5][6][7] Attarbaschi et al 8 recently published a study, on behalf of the BFM cooperative study group, in which they report absolute sensitivity and 0.78 specificity for absence of CD10 expression (CD10À) in pro-B and pre-B ALL as phenotypic marker for predicting MLL rearrangements. Our results show that the absence of CD10 in BP-ALL patients with MLL rearrangements has very low specificity (28/86, 32.56%), while the presence of NG2 accounts for high sensitivity (87-90%) and specificity (99-100%).…”

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

“…This finding is supported by recent studies suggesting that CD10-negative pre-B-ALL cases may represent pro-B-ALL cases that maintain their tendency to rearrange and express their Ig heavy chain. 50,51 A recent study suggested that MLL-AF4-positive infant ALL is initiated later in fetal development than most MLL-AF4-negative childhood B-cell precursor ALL (o3 years), based on the presence and absence of nucleotide insertions at the DH-JH junction, respectively. 22 In line with this observation, nucleotide insertion at the DH-JH junction was present in 73% of MLL-AF4 infant ALL cases in this study.…”

Improved outcome with hematopoietic stem cell transplantation in a poor prognostic subgroup of infants with mixed-lineage-leukemia (MLL)–rearranged acute lymphoblastic leukemia: results from the Interfant-99 Study

“…13 The detection of MLL rearrangements was preferentially based on reverse transcription polymerase chain reaction or MLL split-signal fluorescence in situ hybridization analysis. 2,14 However, classic 11q23 translocations without reverse transcription polymerase chain reaction/ fluorescence in situ hybridization confirmation also counted for MLL ϩ cases. Patients were treated with informed consent from the patient's parents or legal guardians.…”