Acute lymphoblastic leukemia with t(4;11) in children 1 year and older: The ‘big sister’ of the infant disease?

Abstract

The t(4;11)-positive acute lymphoblastic leukemia (ALL) is a rare disease in children above the age of 1 year. We studied the clinical and biological characteristics in 32 consecutively diagnosed childhood cases (median age 10.0 years, range 1.0-17.1 years). Immunophenotyping revealed a pro-B and a pre-B stage in 24 and eight cases, respectively. IGH genes were rearranged in 84% of leukemias with a predominance of incomplete DJ H joints. Whereas IGK-Kde and TCRD rearrangements were rare, TCRG rearrangements were present in 50% of cases and involved mainly Vc11 or Vc9 together with a Jc1.3./2.3 gene segment, an unusual combination among t(4;11)-negative B-cell precursor ALL. Oligoclonality was found in about 30% as assessed by heterogeneous IGH and TCRG rearrangements. Our data are in line with transformation of a precursor cell at an early stage of B-cell development but retaining the potential to differentiate to the pre-B cell stage in vivo. Although a distinct difference between infant and older childhood cases with t(4;11) became evident, no age-related biological features were found within the childhood age group. In contrast to infants with t(4;11)-positive ALL, childhood cases had a relatively low cumulative incidence of relapse of 25% at 3.5 years with BFMbased high-risk protocols.

Chromosome 14 copy number-dependent IGH gene rearrangement patterns in high hyperdiploid childhood B-cell precursor ALL: implications for leukemia biology and minimal residual disease analysis

“…[17][18][19][20] We therefore determined the IGH rearrangements in 130 children with HeH BCP ALL (90 consecutively recruited and 40 selected cases) and correlated their individual sequence and clonality pattern with their respective IGH allele and/or chromosome 14 copy numbers. Our aim was to determine to which extent these IGH rearrangement patterns may be used to delineate monoclonal cases with a trisomy 14 from oligoclonal ones with a disomy 14 and to discuss the implications of our findings for leukemia biology and MRD analysis.…”

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

“…[1][2][3][4] In an early study of childhood t(4;11)-positive ALL, we observed that treatment outcome differed by age group with infants having the worst outcome, 5 a finding that has since been confirmed by many other studies including one published in this issue of Leukemia. [6][7][8] Despite recent improvements in the overall treatment outcome for ALL patients, MLL-AF4 fusion is still associated with a dismal prognosis in infants (especially those younger than 6 months ) and adults. 4,[6][7][8] Of note, a difference in outcome by age has also been observed in cases with the t(9;22)(q34;q11.2) and BCR-ABL fusion.…”

“…[6][7][8] Despite recent improvements in the overall treatment outcome for ALL patients, MLL-AF4 fusion is still associated with a dismal prognosis in infants (especially those younger than 6 months ) and adults. 4,[6][7][8] Of note, a difference in outcome by age has also been observed in cases with the t(9;22)(q34;q11.2) and BCR-ABL fusion. 9 The underlying basis of age differences in outcome among leukemias with the same primary genetic abnormality remains unknown, but has been the subject of many investigations that raise several intriguing hypotheses.…”

“…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.…”

Bimodal distribution of genomic MLL breakpoints in infant acute lymphoblastic leukemia treatment

“…2 With respect to clinical course and biological features, infant leukemia exhibits different characteristics to a phenotypically and cytogenetically similar disease in older age. 3,4 A high rate of breakpoints located in the telomeric portion of the MLL breakpoint cluster region (BCR), similar to therapyinduced acute leukemia associated with topoisomerase II inhibitors, suggested a similar mechanism for MLL rearrangement generation in infant leukemia. Other DNA features, such as scaffold-attachment regions (SAR), DNAse I hypersensitivity sites and initiation sites of apoptotic nucleases, have been discussed to be involved in alternative break mechanisms.…”