Germline Mutation in Leukemia Highlights Disease Complexity

A recent report published in Nature Genetics has underscored the key role that the ETV6 gene plays in platelet formation and leukemia predisposition.1 Researchers pinpointed the gene as a tumor suppressor in childhood leukemia, and identified a trio of ETV6 germline mutations that may contribute to thrombocytopenia, high red blood cell mean corpuscular volume, and leukemia predisposition.

While this research is not the first to find germline mutations in leukemia – investigators at St. Jude Children’s Research Hospital recently identified the PAX5 mutation,2 and investigators at Cleveland Clinic the DDX41 mutation3 – it raises the notion that leukemia is a much more complex entity than we currently think it is, corresponding author Jorge Di Paola, MD, explained to ASH Clinical News.

What is the main take-home message of the study? “There might be more to the malignant transformation of the bone marrow than we realize,” said Dr. Di Paola, of the University of Colorado Anschutz Medical Campus (AMC) in Aurora, Colorado. “Now that we’ve discovered these mutations, there are databases out there with tons of families in them with these germline mutations, so I hope institutions check for them.”

In the current study, lead author Leila Noetzli, a PhD candidate at AMC, and colleagues screened 23 families, eventually identifying one with autosomal dominant thrombocytopenia, high erythrocyte mean corpuscular volume, and two occurrences of B-cell–precursor acute lymphocytic leukemia (ALL). Whole-exome sequencing identified mutations in the ETV6 gene that partially disrupt the gene’s transcriptional repression in vitro and cause aberrant cytoplasmic localization of both mutant and endogenous ETV6, suggesting a dominant-negative effect.

“The identified mutations in ETV6 also impair megakaryocyte development and proplatelet formation in culture,” the authors noted.

Dr. Di Paola acknowledged that most cases of leukemia are not inherited or predisposed by genetics but, he added, “Eventually, when you see a high number of leukemia cases in a family, [a potentially genetic cause] is something to look at. We have seen that p53 and other mutations are frequent in cancers, but there are more mutations being identified that seem to predispose people to cancer.”

The researchers also found several genetic variants and a new gene fusion between PAX5 and SHB in the leukemia sample that were not present in a remission sample.

PAX5 has been associated with leukemia and this PAX5/SHB fusion seems to be the most likely culprit,” Dr. Di Paola observed. His lab, along with co-investigator Christopher Porter, MD, also at AMC, is working on recreating the PAX5/SHB mutation in an animal model and in cell lines.

How will the findings from ETV6 germline mutation research fit into clinical practice? More study is needed before definitively answering that question, Dr. Di Paola stated. He pointed out that not everyone who inherited the mutations, even in the largest family in which members developed leukemia in the study, eventually developed the disease, which indicates that there may be other factors that “coalesce with these mutations to cause leukemia.”

“The other issue is that even in our patients that have leukemia that went into remission, the germline mutation persists,” he noted. “If we follow these patients more closely and thoroughly, are they likely to get other cancers? We don’t know the answer to that.”

“At this point, we are looking to learn more from the natural history of these cancers so that we can talk about patient counseling,” he added.


  1. Noetzli L, Lo R, Lee-Sherick A, et al. Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia. Nat Genet. 2015;5:535-8.
  2. Liu G, Cimmino L, Jude J, et al. Pax5 loss imposes a reversible differentiation block in B-progenitor acute lymphoblastic leukemia. Genes & Development. 2014;28:1337-50.
  3. Polprasert C, Schulze I, Sekeres MA, et al. Inherited and somatic defects in DDX41 in myeloid neoplasms. Cancer Cell. 2015;27:658-70.