Cryptic and atypical KMT2A‐USP2 and KMT2A‐USP8 rearrangements identified by mate pair sequencing in infant and childhood leukemia

@article{Blackburn2020CrypticAA,
  title={Cryptic and atypical KMT2A‐USP2 and KMT2A‐USP8 rearrangements identified by mate pair sequencing in infant and childhood leukemia},
  author={Patrick R. Blackburn and James B. Smadbeck and Iya Y Znoyko and Matthew R. Webley and Beth A. Pitel and George Vasmatzis and Xinjie Xu and Patricia T Greipp and Nicole L. Hoppman and Rhett P Ketterling and Linda B. Baughn and Kathryn G Lindsey and Cynthia A. Schandl and Daynna J. Wolff and Jess F Peterson},
  journal={Genes},
  year={2020},
  volume={59},
  pages={422 - 427}
}
Infant leukemias are a rare group of neoplasms that are clinically and biologically distinct from their pediatric and adult counterparts. Unlike leukemia in older children where survival rates are generally favorable, infants with leukemia have a 5‐year event‐free survival rate of <50%. The majority of infant leukemias are characterized by KMT2A (MLL) rearrangements (~70 to 80% in acute lymphoblastic leukemia), which appear to be drivers of early leukemogenesis. In this report, we describe… 
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References

SHOWING 1-10 OF 24 REFERENCES
Whole transcriptome sequencing reveals a KMT2A‐USP2 fusion in infant acute myeloid leukemia
Infant acute lymphoblastic leukemia with lysine (K)‐specific methyltransferase 2A (KMT2A) rearrangements usually has a poor prognosis regardless of the fusion partners of KMT2A. However, the
The MLL recombinome of acute leukemias in 2017
TLDR
This study provides a comprehensive analysis of the MLL recombinome in acute leukemia and demonstrates that the establishment of patient-specific chromosomal fusion sites allows the design of specific PCR primers for minimal residual disease analyses for all patients.
The landscape of somatic mutations in Infant MLL rearranged acute lymphoblastic leukemias
TLDR
Infant acute lymphoblastic leukemia (ALL) with MLL rearrangements (MLL-R) represents a distinct leukemia with a poor prognosis and has one of the lowest frequencies of somatic mutations of any sequenced cancer, with the predominant leukemic clone carrying a mean of 1.3 non-silent mutations.
Environmental and genetic susceptibility to MLL-defined infant leukemia.
  • J. Ross
  • Medicine, Biology
    Journal of the National Cancer Institute. Monographs
  • 2008
TLDR
There is increasing evidence that environmental and genetic factors may contribute to the risk of MLL-defined infant leukemias, and there is a unique opportunity to integrate epidemiological data with laboratory data on MLL status and genotype.
Acute lymphoblastic leukemia in infancy
TLDR
Current research efforts to improve the outcome of MLL‐rearranged ALL in infants include clinical trials testing cytarabine‐intensive regimens and translational investigations of novel, targeted therapies, such as FLT3‐inhibitors.
Human MLL/KMT2A gene exhibits a second breakpoint cluster region for recurrent MLL–USP2 fusions
TLDR
Nearly, all breakpoints have been identified in the major breakpoint cluster region (BCR) of the MLL gene (MLL exons 8–14) and some of the patients remained negative, although they were positively prescreened by various methods.
Leukemogenic rearrangements at the mixed lineage leukemia gene (MLL)—multiple rather than a single mechanism
TLDR
The MLL destabilizing signaling pathways under discussion, namely early apoptotic DNA fragmentation, transcriptionStalling, and replication stalling, may all act in concert upon infection-, transplantation-, or therapy-induced cell cycle entry of hematopoietic stem and progenitor cells (HSPCs), to permit misguided cleavage and error-prone DNA repair in the cell-of-leukemia-origin.
Updates in the biology and therapy for infant acute lymphoblastic leukemia
TLDR
Advances in molecular profiling and integration of targeted therapy have the potential to reduce toxicity and improve survival for infants with ALL.
Systematic Classification of Mixed-Lineage Leukemia Fusion Partners Predicts Additional Cancer Pathways
TLDR
A solution is proposed for an obvious problem, namely why so many and completely different MLL fusion alleles are always leading to the same leukemia phenotypes (ALL, AML, or MLL).
The genetic basis and cell of origin of mixed phenotype acute leukaemia
TLDR
A large-scale genomics study shows that the cell of origin and founding mutations determine disease subtype and lead to the expression of multiple haematopoietic lineage-defining antigens in mixed phenotype acute leukaemia.
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