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

Bueno, Clara; Ayllón, Verónica; Montes, Rosa; Navarro-Montero, Óscar; Ramos-Mejía, Verónica; Real, Pedro J.; Romero‐Moya, Damià; Araúzo-Bravo, Marcos J.; Menéndez, Pablo

doi:10.1182/blood-2012-11-470146

Cited by 37 publications

(32 citation statements)

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“…In hESCs, enforced expression of FLT3-TKD/FLT3-WT abolished hematopoietic specification, 118 whereas it conveyed a transient overexpansion but did not suffice to immortalize/transform MA4-expressing CB-CD34 1 HSPCs 119 ( Table 2).…”

Section: Available Disease Models For T(4;11) 1 B-allmentioning

confidence: 99%

“…Studies from our laboratory addressed whether these populations constitute target cells for leukemia initiation. [116][117][118][119] Lentiviral-mediated expression of MA4 failed to transform either hESC blood derivatives or CB-derived CD34 HSPCs. 116,117 Other sources of developmentally early stem cells which might be potential cells of origin are fetal liver and aorta-gonadmesonephros (AGM) cells.…”

Section: Available Disease Models For T(4;11) 1 B-allmentioning

confidence: 99%

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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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105

138

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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: Available Disease Models For T(4;11) 1 B-allmentioning

confidence: 99%

Section: Available Disease Models For T(4;11) 1 B-allmentioning

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

Self Cite

105

138

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“…4 In contrast, in older children the percentages of MLL rearrangements are 6% and 14% for ALL and AML, respectively. 5 There is evidence from multiple in vitro systems that the presence of a MLL rearrangement is insufficient by itself to drive leukemogenesis, 6, 7, 8 suggesting that additional factors are required in the presence (and absence) of MLL rearrangements to drive leukemogenesis. In contrast, very little is known about the role of congenital variation in MLL− IL.…”

Section: Introductionmentioning

confidence: 99%

Excess congenital non-synonymous variation in leukemia-associated genes in MLL− infant leukemia: a Children’s Oncology Group report

et al. 2013

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Infant leukemia (IL) is a rare sporadic cancer with a grim prognosis. While most cases are accompanied by MLL-rearrangements and harbor very few somatic mutations; less is known about the genetics of the cases without MLL translocations. We performed the largest exome sequencing study to date on matched non-cancer DNA from pairs of mothers and IL patients to characterize congenital variation that may contribute to early leukemogenesis. Using the COSMIC database to define acute leukemia-associated candidate genes, we find a significant enrichment of rare, potentially functional congenital variation in IL patients compared to randomly selected genes within the same patients and unaffected pediatric controls. IL AML patients had more overall variation than IL ALL patients, but less of that variation was inherited from mothers. Of our candidate genes, we found that MLL3 was a compound heterozygote in every infant who developed AML and 50% of infants who developed ALL. These data suggest a model by which known genetic mechanisms for leukemogenesis could be disrupted without an abundance of somatic mutation or chromosomal rearrangements. This model would be consistent with existing models for the establishment of leukemia clones in utero and the high rate of IL concordance in monozygotic twins.

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“…This caused a reduction in the CDKN1B (p27kip1) protein level in an in vivo model [66]. Patients with MLL rearrangement also exhibit elevated expression of FMS-like tyrosine kinase 3 (FLT3) gene [67]. The t(11;19) translocation leads to the fusion of the MLL gene to 1/eleven-nineteen-leukemia (MLLT1/ENL).…”

Section: Mll Translocationsmentioning

confidence: 99%

Acute Lymphoblastic Leukemia: Genetic Events and Molecular Signatures

Hu¹

2014

Am. J. Biomed. Sci.

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

Abstract: Key Points FLT3 activation cooperates with the MLL-AF4 fusion gene to fully abolish blood formation from hESCs. FLT3 activation does not cooperate with the MLL-AF4 fusion oncogene to transform hESCs or hESC-derived hematopoietic progeny.

Cited by 37 publications

References 50 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

Excess congenital non-synonymous variation in leukemia-associated genes in MLL− infant leukemia: a Children’s Oncology Group report

Acute Lymphoblastic Leukemia: Genetic Events and Molecular Signatures

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