Genomic subtyping and therapeutic targeting of acute erythroleukemia.

Nat Genet 2019 04 29;51(4):694-704. Epub 2019 Mar 29.

Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.

Acute erythroid leukemia (AEL) is a high-risk leukemia of poorly understood genetic basis, with controversy regarding diagnosis in the spectrum of myelodysplasia and myeloid leukemia. We compared genomic features of 159 childhood and adult AEL cases with non-AEL myeloid disorders and defined five age-related subgroups with distinct transcriptional profiles: adult, TP53 mutated; NPM1 mutated; KMT2A mutated/rearranged; adult, DDX41 mutated; and pediatric, NUP98 rearranged. Genomic features influenced outcome, with NPM1 mutations and HOXB9 overexpression being associated with a favorable prognosis and TP53, FLT3 or RB1 alterations associated with poor survival. Targetable signaling mutations were present in 45% of cases and included recurrent mutations of ALK and NTRK1, the latter of which drives erythroid leukemogenesis sensitive to TRK inhibition. This genomic landscape of AEL provides the framework for accurate diagnosis and risk stratification of this disease, and the rationale for testing targeted therapies in this high-risk leukemia.

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-019-0375-1DOI Listing
April 2019
17 Reads
29.352 Impact Factor

Publication Analysis

Top Keywords

genomic features
8
high-risk leukemia
8
hoxb9 overexpression
4
overexpression associated
4
mutations hoxb9
4
npm1 mutations
4
influenced outcome
4
outcome npm1
4
associated favorable
4
rb1 alterations
4
alterations associated
4
flt3 rb1
4
tp53 flt3
4
favorable prognosis
4
prognosis tp53
4
features influenced
4
rearranged genomic
4
mutated npm1
4
npm1 mutated
4
tp53 mutated
4

References

(Supplied by CrossRef)

Cancer Genome Atlas Research Network et al.
N. Engl. J. Med. 2013

E Papaemmanuil et al.
N. Engl. J. Med. 2016

N Cervera et al.
Leukemia 2016

V Grossmann et al.
Leukemia 2013

N Ping et al.
Leukemia 2017

W Liu et al.
Mod. Pathol. 2011

AM Almeida et al.
Int. J. Mol. Sci. 2017

W Dameshek et al.
Blood 1958

JM Bennett et al.
Ann. Intern. Med. 1985

JW Vardiman et al.
Blood 2009

DA Arber et al.
Blood 2016

Similar Publications