- Acute megakaryocytic leukemia (AMKL) occurring in children without Down's syndrome is generally associated with a poorer prognosis.
- Standard recommendation is to treat AMKL in children without Down's
syndrome with allogeneic stem
- Genetic screening has identified mutations in these
patients that can lead to aggressive disease a poor prognosis.
- The genetic screening of
non-Down's syndrome children with AMKL
helps identify patients who require allogeneic stem cell
transplant and those who do not.
Mutations that cause
aggressive acute megakaryocytic leukemia in children without Down's syndrome could help determine mode of management according to a recent study
conducted by St. Jude Children's Research Hospital.
Acute Megakaryocytic Leukemia
Acute megakaryocytic leukemia (AMKL) is a type
of acute leukemia
involving the megakaryocytes
in the bone marrow, from which platelets (blood cells that form clot) are
‘Genetic screening identifies mutations that cause aggressive megakaryocytic leukemia in pediatric patients, a finding that might lead to newer treatment recommendations.’
AMKL is generally rare in the adult
population, but is responsible for about 10 percent of pediatric cases of acute
myeloid leukemia (AML).
The research team at St Jude Children's Research Hospital hoped
to identify children suffering from acute megakaryocytic leukemia, who might
benefit from allogeneic stem cell transplant from a genetically matched donor.
The genetic basis of AMKL
in children with Down's syndrome has been identified and carries a good prognosis
but the cause remains a mystery in about 40 percent of the remaining cases.
Current recommendation is to treat all AMKL cases in children without Down's
syndrome with stem cell transplant, since AMKL in children without Down's
syndrome generally carries an unfavorable prognosis.
"Because long-term survival for pediatric
AMKL patients without Down's syndrome is poor, just 14 to 34 percent, the
standard recommendation by many pediatric oncologists has been to treat all patients
with allogeneic stem cell transplantation during their first remission,"
said senior and co-corresponding author Tanja Gruber, M.D., Ph.D., an associate
member of the St. Jude Department of Oncology.
this study, we identified several genetic alterations that are important
predictors of treatment success," she said. "All newly identified
pediatric AMKL patients without Down's syndrome should be screened for these
prognostic indicators at diagnosis. The results will help identify which patients
need allogeneic stem cell transplants during their first remission and which do
of the Study
In the study, the scientists undertook new generation genetic sequencing
of the entire exome or RNA of 89 children without Down's syndrome
from acute megakaryocytic leukemia. Additionally, they analyzed patient's gene
expression and long term survival.
High Risk Mutations Identified in
The mutations found in AMKL cases without
Down's syndrome included the fusion
KMT2A and NUP98-KDM5A,
all of which
are associated with poorer long term survival in comparison to other pediatric
Fusion genes are created when genes break and again assemble. Such
fusion cause secretion of abnormal cellular proteins that cause unchecked cell
proliferation and other changes that cause development of cancer.
The research group also recommended testing all pediatric AMKL cases for
GATA-1 gene mutations. Mutations in the GATA-1 gene are typically seen in
children with Down's syndrome which is an indicator of good
prognosis. Similarly, the authors found that non-Down's syndrome children having the GATA-1 gene mutation and no fusion gene had an
excellent long term survival rate.
"The results raise the
possibility that pediatric AMKL patients
without Down's syndrome who have
mutations in GATA1 may benefit from the same reduced chemotherapy
used to treat the leukemia
in patients with Down's syndrome," Gruber said.
Findings of the Study
The results of the study showed that non-Down's
syndrome pediatric patients with AMKL can
be subdivided into seven subgroups
based on the genetic mutation, gene expression and long-term prognosis.
A new subgroup identified was the HOX subgroup
in which about 15 percent of the 89 participants came under. Normally, the HOX
genes control development, but mutations can cause leukemia
The investigators also found cooperating
mutations that help in increasing the risk of developing AMKL in the different
subgroups. These cooperating mutations include alterations in the RB1 gene and
mutations in the RAS and JAK pathways
in cells. Interestingly, similar
changes have been identified in other cancers as well.
In conclusion, the genetic screening and
treatment recommendations of the study are currently being followed at St Jude
and the authors hope their research will pave the way for new treatment
guidelines in pediatric AMKL cases elsewhere as well.
- Jasmijn D E de Rooij, Cristyn Branstetter, Jing Ma, Yongjin Li, Michael P Walsh, Jinjun Cheng, Askar Obulkasim, Jinjun Dang, John Easton, Lonneke J Verboon, Heather L Mulder, Martin Zimmermann, Cary Koss, Pankaj Gupta, Michael Edmonson, Michael Rusch, Joshua Yew Suang Lim, Katarina Reinhardt, Martina Pigazzi, Guangchun Song, Allen Eng Juh Yeoh, Lee-Yung Shih, Der-Cherng Liang, Stephanie Halene, Diane S Krause, Jinghui Zhang, James R Downing, Franco Locatelli, Dirk Reinhardt, Marry M van den Heuvel-Eibrink, C Michel Zwaan, Maarten Fornerod, Tanja A Gruber. Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes. Nature Genetics, 2017; DOI: 10.1038/ng.3772
- CBFA2T3-GLIS2 fusion transcript is a novel common feature in pediatric, cytogenetically normal AML, not restricted to FAB M7 subtype - (http://www.bloodjournal.org/content/121/17/3469?sso-checked=true)