Protracted postnatal natural histories in childhood leukemia

Maia, Ana-Teresa; Koechling, Joachim; Corbett, Robin; Metzler, Markus; Wiemels, Joseph L.; Greaves, Mel

doi:10.1002/gcc.20003

Cited by 59 publications

(42 citation statements)

References 25 publications

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“…There have been case reports of later onset childhood MLL-R leukemia and one report of a 6-year-old with MLL-R leukemia who had a positive blood spot at birth. 19 What does seem clear is that short latency concordance of infant MLL-R leukemia in monozygotic twins is not universal.…”

Section: Mll-enl Rt-pcr and Mll Fish Results From Twins A And B Are Smentioning

confidence: 99%

Discordance of MLL-rearranged (MLL-R) infant acute lymphoblastic leukemia in monozygotic twins with spontaneous clearance of preleukemic clone in unaffected twin

Chuk

McIntyre

Small

et al. 2009

Blood

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Concordance of MLL-rearranged acute leukemia in infant monozygotic twins is thought to be 100% with a very short latency period, suggesting that either the MLL fusion itself is sufficient to cause leukemia or that it promotes the rapid acquisition of additional oncogenic events that result in overt disease. We report the first case of discordance in an infant monozygotic twin pair. Twin A presented at age 9 months with MLL-ENL ؉ acute lymphoblastic leukemia and twin B remains healthy 3 years later. IntroductionReported concordance rates for acute leukemia in monozygotic twins range from less than 5% to 100%, depending on the age of twin A at diagnosis and the cytogenetics of the leukemia. 1 Many reports of twin concordance have documented identical, clonal, nonconstitutional fusion sequences in both twins, suggesting that in these cases a preleukemic clone developed during the prenatal period in one twin and was transferred to the other by placental anastomoses. 2,3 Up to 80% of infant leukemias possess rearrangement of the MLL gene at 11q23, most commonly fused with the AF4, ENL, or AF9 genes. 4 These leukemias have a very short latency period, with diagnosis occurring at an average age of 6 months. Although the number of reported cases is small, the concordance rate for infant monozygotic twins with MLL-rearranged (MLL-R) leukemia is thought to be 100%. 1 The rapid transition to leukemia (which is also seen in therapy-associated MLL-R leukemias) and high twin concordance have led some to speculate that MLL fusions alone are sufficient for the development of leukemia. This view is supported by recent studies showing a striking paucity of copy number alterations (CNAs) in cases of MLL-R acute lymphoblastic leukemia (ALL) compared with other leukemias. 5 However, data from MLL-R transgenic murine models strongly suggest that additional events are required for the development of leukemia. 6,7 Others have suggested that MLL fusions may promote genetic instability, rapid clonal expansion, epigenetic events, or defective DNA damage repair, leading to the rapid development of disease. 1 It is possible that such events are undetectable at the resolution of the CNA studies.The concordance rate for leukemia in monozygotic twins in childhood (index case older than 1 year) is much lower (approximately 10%). 1 There is often a long latency period, as seen in a set of twins with ETV6/RUNX1 ALL diagnosed at 5 and 14 years of age. Retrospective analysis of bone marrow from the second twin showed the presence of clonal ETV6/RUNX1 ϩ cells at the time of diagnosis of the sibling 9 years earlier. 8 Many childhood leukemias are thought to initiate prenatally. Retrospective analyses of neonatal blood spots from children diagnosed with leukemia years later have shown the presence of cells with identical clonal fusion sequences. This phenomenon is especially common in younger children with a t(12;21) ETV6/RUNX1 translocation or hyperdiploidy and is distinctly uncommon in cases in older children or those with a t(1;19) E2A/PBX1 transl...

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Section: Mll-enl Rt-pcr and Mll Fish Results From Twins A And B Are Smentioning

confidence: 99%

Discordance of MLL-rearranged (MLL-R) infant acute lymphoblastic leukemia in monozygotic twins with spontaneous clearance of preleukemic clone in unaffected twin

Chuk

McIntyre

Small

et al. 2009

Blood

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“…In infant leukemias, MLL gene fusions arise in utero (Ford et al, 1993;Gale et al, 1997) and usually present clinically within a few months, although rare cases of protracted latency have been recorded (Maia et al, 2004). The fact that high grade malignancies can evolve so rapidly is unusual and raises interesting questions relating to underlying mechanisms of molecular pathogenesis and the requirements for multiple genetic events.…”

Section: Discussionmentioning

confidence: 99%

Covert preleukemia driven by MLL gene fusion

Zuna

Burjanivová

Mejstříková

et al. 2008

Genes Chromosomes & Cancer

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Acute leukemia is considered to be a two-or multiple-step process. Although there is a considerable knowledge regarding the character of the ''first hit,'' the nature of the ''second hit'' remains unanswered in most of the cases including leukemias with MLL gene rearrangement. We demonstrate here a striking sequence of events, which include a covert, protracted preleukemic phase characterized by a dominant MLL/FOXO3A clone with intact myeloid differentiation and the subsequent acquisition of a secondary genetic abnormality, leading to overt lymphoblastic leukemia. Backtracking of the secondary acute lymphoblastic leukemia (sALL) with the MLL rearrangement showed no blasts in the bone marrow (BM) during the protracted preleukemic phase. However, at the same time (more than 1 year before the sALL diagnosis) the MLL/FOXO3A was present in up to 90% of BM cells including myeloid lineage, suggesting that the fusion arose in a multipotent progenitor. To identify potential ''second hit'' precipitating sALL we compared DNA in preleukemic versus fully leukemic samples. The analysis revealed a 10 Mb gain on 19q13.32 in the sALL, absent in the preleukemic specimen. These data provide insight into the dynamics of leukemogenesis in secondary leukemia with MLL rearrangement.

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“…First, the protracted postnatal interval, or latency, before disease diagnosis can be up to a decade or more (Wiemels et al, 1999b;Maia et al, 2004) and concordance rates in twins are modest at B10% . This suggests that additional or secondary and complementary genetic events are required.…”

Section: An Initiating Role For Tel-aml1 In Pathogenesis Of Childhoodmentioning

confidence: 99%

Role of the TEL-AML1 fusion gene in the molecular pathogenesis of childhood acute lymphoblastic leukaemia

2004

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Balanced chromosomal translocations are frequently associated with haematopoietic neoplasms and often involve genes that encode transcription factors, which play critical roles in normal haematopoiesis. Fusion oncoproteins that arise from chimeric genes generated by such translocations are usually stable and consistent molecular markers for a given disease subtype and contribute to the leukaemogenic processes. The t(12;21)(p13;q22) chromosomal translocation is the most frequent illegitimate gene recombination in paediatric cancer, occurring in approximately 25% of common (c) B-cell precursor acute lymphoblastic leukaemia (cALL) cases. The rearrangement results in the in-frame fusion of the 5 0 region of the ETS-related gene, TEL (ETV6), to almost the entire AML1 (RUNX1) locus and is associated with favourable prognosis following conventional therapeutic strategies. We discuss here the prenatal origins of the TEL/AML1 translocation as an initiating mutation, the role of TEL-AML1 in cellular transformation and the molecular mechanisms by which the chimeric protein imposes altered patterns of gene expression.

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Protracted postnatal natural histories in childhood leukemia

Cited by 59 publications

References 25 publications

Discordance of MLL-rearranged (MLL-R) infant acute lymphoblastic leukemia in monozygotic twins with spontaneous clearance of preleukemic clone in unaffected twin

Discordance of MLL-rearranged (MLL-R) infant acute lymphoblastic leukemia in monozygotic twins with spontaneous clearance of preleukemic clone in unaffected twin

Covert preleukemia driven by MLL gene fusion

Role of the TEL-AML1 fusion gene in the molecular pathogenesis of childhood acute lymphoblastic leukaemia

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