Absence of global hypomethylation in promoter hypermethylated Mixed Lineage Leukaemia-rearranged infant acute lymphoblastic leukaemia

Stumpel, Dominique J.P.M.; Schneider, Pauline; Roon, Eddy H.J. Van; Pieters, Rob; Stam, Ronald W.

doi:10.1016/j.ejca.2012.07.013

Cited by 33 publications

(32 citation statements)

References 36 publications

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“…However, Stumpel et al reported that MLL-r infant B-ALL cells display a global hypermethylated genomic state, both at promoter and nonpromoter regions. 105 Because global hypomethylation usually leads to genomic instability linked to cancer development, this study might explain the global genomic stability/silent mutational landscape found in MA4 1 infant B-ALLs and the remarkable sensitivity of MLL-r cells to demethylating agents. 106 Further studies from Stumpel et al focused on genome-wide cytosine guanine dinucleotide island methylation and promoter methylation.…”

Section: 103mentioning

confidence: 99%

Revisiting the biology of infant t(4;11)/MLL-AF4+ B-cell acute lymphoblastic leukemia

Sanjuán-Pla

Bueno

Prieto

et al. 2015

Blood

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137

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Infant B-cell acute lymphoblastic leukemia (B-ALL) accounts for 10% of childhood ALL. The genetic hallmark of most infant B-ALL is chromosomal rearrangements of the mixed-lineage leukemia (MLL) gene. Despite improvement in the clinical management and survival (∼85-90%) of childhood B-ALL, the outcome of infants with MLL-rearranged (MLL-r) B-ALL remains dismal, with overall survival <35%. Among MLL-r infant B-ALL, t(4;11)+ patients harboring the fusion MLL-AF4 (MA4) display a particularly poor prognosis and a pro-B/mixed phenotype. Studies in monozygotic twins and archived blood spots have provided compelling evidence of a single cell of prenatal origin as the target for MA4 fusion, explaining the brief leukemia latency. Despite its aggressiveness and short latency, current progress on its etiology, pathogenesis, and cellular origin is limited as evidenced by the lack of mouse/human models recapitulating the disease phenotype/latency. We propose this is because infant cancer is from an etiologic and pathogenesis standpoint distinct from adult cancer and should be seen as a developmental disease. This is supported by whole-genome sequencing studies suggesting that opposite to the view of cancer as a “multiple-and-sequential-hit” model, t(4;11) alone might be sufficient to spawn leukemia. The stable genome of these patients suggests that, in infant developmental cancer, one “big-hit” might be sufficient for overt disease and supports a key contribution of epigenetics and a prenatal cell of origin during a critical developmental window of stem cell vulnerability in the leukemia pathogenesis. Here, we revisit the biology of t(4;11)+ infant B-ALL with an emphasis on its origin, genetics, and disease models.

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Section: 103mentioning

confidence: 99%

Revisiting the biology of infant t(4;11)/MLL-AF4+ B-cell acute lymphoblastic leukemia

Sanjuán-Pla

Bueno

Prieto

et al. 2015

Blood

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137

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“…methylated genomic state and respond well to demethylating agents, leading to apoptosis in these cells. 53,54 In addition, leukemiaspecific histone modifications such as H3K79 dimethylation induced via DOT1L recruitment by MLL fusion proteins can be effectively modulated by histone deacetylase (HDAC) inhibitors. 55 These findings support the use of demethylating agents and/or HDAC inhibitors that might reverse the inherent resistance to chemotherapy for infant MLL-r ALL.…”

Section: Histone Deacetylase Inhibitorsmentioning

confidence: 99%

Recent progress in the treatment of infant acute lymphoblastic leukemia

Tomizawa

2015

Pediatrics International

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Treatment of infants with acute lymphoblastic leukemia (ALL), especially those with mixed lineage leukemia (MLL) rearrangement (MLL-r), which account for approximately 80% of cases, is still a major challenge for pediatric hematologists and oncologists worldwide. Continuing efforts by collaborative clinical study groups in Europe, North America, and Japan have rescued approximately half of the MLL-r ALL patients with intensive chemotherapy with or without allogeneic hematopoietic stem cell transplantation. Recent progress has clarified the unique mechanism of MLL-r ALL: the aberrant methylation and histone modifications via DOT1L and other related molecules by MLL fusion proteins lead to leukemogenetic gene expression, thus to overt leukemia. In order to overcome this dismal subtype of ALL, novel targeted therapy based on leukemia biology is urgently needed. Due to the extreme rarity of the disease, collaboration between the study groups in Europe (Interfant), North America (Children's Oncology Group), and Japan (Japanese Pediatric Leukemia/Lymphoma Study Group) is under way.Key words acute lymphoblastic leukemia, epigenetics, hematopoietic stem cell transplantation, infant, mixed lineage leukemia.Acute lymphoblastic leukemia (ALL), a malignant disorder of lymphoid progenitor cells, is the most common type of malignant neoplasms in children and adolescents, with approximately 444-532 cases diagnosed annually in Japan. 1 Optimal use of "old drugs", developed between the 1950s and 1970s under successive collaborative clinical trials, has improved the outcome of childhood ALL to achieve an event-free survival (EFS) rate of 80.4-87.2% and an overall survival (OS) rate of 91.8-93.5% in recently completed clinical trials. [2][3][4][5] The progress in the treatment of infant ALL (diagnosed at age <12 months), however, is lagging behind compared with the treatment of children ≥1 year: EFS and OS remain at 41.7-50.9% and 44.8-60.5%, respectively (Table 1). 9,[11][12][13] In this review, advances in the pathobiology and clinical management of ALL in infants is described. Epidemiology and characteristicsInfant ALL accounts for <5% of childhood ALL, with 20-25 new cases diagnosed annually in Japan. In children ≥1 year, ALL comprises 75-80% of all childhood leukemia because of the high peak incidence of B-lineage ALL between the age of 2 and 5 years, with a predominance in boys. In contrast, the incidence of ALL in infants is the same as that of acute myeloid leukemia (AML), with a slight predominance in girls. 1,11 Biologically and clinically, infant ALL consists of two distinct subtypes: one involves rearrangements of mixed lineage leukemia (MLL also called KMT2A), which accounts for approximately 80% of infant ALL; and the other with germline MLL. Infant ALL with rearranged MLL (MLL-r) is a highly aggressive leukemia with high white blood cell (WBC) count and frequent involvement of extramedullary sites including the central nervous system (CNS) at diagnosis. 9,11 In addition, MLL-r ALL has a very immature CD10-ne...

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“…48,49 In contrast to many human cancers, which are commonly characterized by hypomethylation in nonpromoter regions, MLL-AF41 ALL displays genome-wide hypermethylation at nonpromoter sequences. 48,49 Global hypomethylation is usually associated with genomic instability, allowing additionally acquired genetic hits to propel a premalignant clone into a fully transformed state. The global hypermethylation of MLL-AF41 ALL might explain why additional genetic lesions have not been discovered in MLLrearranged ALL.…”

Section: Cd34mentioning

confidence: 99%

FLT3 activation cooperates with MLL-AF4 fusion protein to abrogate the hematopoietic specification of human ESCs

Bueno

Ayllón

Montes

et al. 2013

Blood

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Absence of global hypomethylation in promoter hypermethylated Mixed Lineage Leukaemia-rearranged infant acute lymphoblastic leukaemia

Cited by 33 publications

References 36 publications

Revisiting the biology of infant t(4;11)/MLL-AF4+ B-cell acute lymphoblastic leukemia

Revisiting the biology of infant t(4;11)/MLL-AF4+ B-cell acute lymphoblastic leukemia

Recent progress in the treatment of infant acute lymphoblastic leukemia

FLT3 activation cooperates with MLL-AF4 fusion protein to abrogate the hematopoietic specification of human ESCs

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