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Pediatric Leukemia Carrying High Risk Mutations Identified, with Possible Impact on Current Treatment

Written by Dr. Lakshmi Venkataraman, MD
Article Reviewed by 
The Medindia Medical Review Team on January 24, 2017 at 11:55 AM
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  • 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 cell transplant.
  • 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 produced.

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High Risk Mutations in Pediatric Leukemia Patients
Pediatric Leukemia Carrying High Risk Mutations Identified, with Possible Impact on Current Treatment

AMKL is generally rare in the adult population, but is responsible for about 10 percent of pediatric cases of acute myeloid leukemia (AML).

Aim of Study

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. 

"In 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 not."

Details 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 suffering from acute megakaryocytic leukemia. Additionally, they analyzed patient's gene expression and long term survival.

High Risk Mutations Identified in Pediatric AMKL

The mutations found in AMKL cases without Down's syndrome included the fusion genes CBFA2T3-GLIS2, KMT2A and NUP98-KDM5A, all of which are associated with poorer long term survival in comparison to other pediatric AMKL subtypes. 

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.

Other 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 and other cancers.

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.

References :
  1. 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
  2. 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)
Source: Medindia

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