Infections may trigger leukemia in the genetically susceptible

 

MADRID – The evidence thus far comes only from animal models, but commonly encountered childhood infections may be able to trigger the development of leukemia in those children with certain genetic predispositions to B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

Mice genetically modified to mimic BCP-ALL susceptibility and its most common subtype (ETV6-RUNX1 BCP-ALL) developed leukemia only after exposure to a common infectious environment.

The findings suggest that common pathogens could trigger childhood BCP-ALL in children with genetic mutations that lead to the loss of function of the Pax5 tumor suppressor gene or to a common translocation in the ETV6-RUNX1 pathway, said Julia Hauer, MD, of Heinrich-Heine University Duesseldorf (Germany).

“The mechanism that takes place in preleukemic cells after the mice were exposed to infection was different in the two mouse models,” she said at a briefing prior to her presentation of the data at the annual congress of the European Hematology Association.

“This is another piece that will, hopefully, contribute to the picture of how exposure to infection can contribute to leukemic development” and may lead to novel approaches for leukemia prevention, she added.

The possibility that exposure to infectious pathogens could trigger leukemia has been bandied about for a century, based in part on observations that leukemia is the most common malignancy in children, with a still unexplained peak incidence between the ages of 2 and 6 years, Dr. Hauer noted.

To explore a possible link, she and her colleagues developed and characterized the aforementioned mice mimicking BCP-ALL with the BCR-ABL1 transcription and ETV6-RUNX1 BCP-ALL, in addition to a previously described Pax5+/- infection model. Some of all three mouse models were exposed not to specific pathogens but to a common laboratory environment, where they could be expected to acquire various infections at 2-3 months of age, and some were kept in a sterile environment designed to reduce transmission of pathogens. Wild-type mice were used as controls.

They observed that the Pax5+/- and ETV6-RUNX1 mice developed BCP-ALL only after exposure to common pathogens. In contrast, the BCR-ABL1p190 mice developed BCP-ALL independent of exposure to common infection.

They also determined that the mechanism leading to leukemia in the Pax5+/- mice was related to constitutive activations of mutations in the Janus kinase (JAK)3 pathway in susceptible B cell precursors, whereas the ETV6-RUNX1 mice developed BCP-ALL at a low penetrance (10.75%, 10 of 93) with a CD19-positive, B220-positive, immunoglobulin M-negative cell surface phenotype, manifested by blast cells in peripheral blood and a clonal immature B-cell receptor rearrangement.

In mice, norovirus and hepatitis C virus may be some of the pathogens most closely linked to risk of leukemia, but it’s likely that other viruses and parasitic infections will turn out to be the culprits in humans, Dr. Hauer said.

The findings raise the possibility of an unexpected link between leukemia and the so-called “hygiene hypothesis” linking childhood asthma, allergies, and atopic skin conditions to a lack of early exposure to a multiplicity of pathogens. In many developed countries, children are relatively protected from exposure to many different pathogens and may not encounter infectious agents until entering preschool or kindergarten, Dr. Hauer commented.

The study was supported by German Cancer Aid, the Jose Carreras Leukemia Foundation, and other charitable agencies. Dr. Hauer reported no relevant disclosures.

[email protected]

 

MADRID – The evidence thus far comes only from animal models, but commonly encountered childhood infections may be able to trigger the development of leukemia in those children with certain genetic predispositions to B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

Mice genetically modified to mimic BCP-ALL susceptibility and its most common subtype (ETV6-RUNX1 BCP-ALL) developed leukemia only after exposure to a common infectious environment.

The findings suggest that common pathogens could trigger childhood BCP-ALL in children with genetic mutations that lead to the loss of function of the Pax5 tumor suppressor gene or to a common translocation in the ETV6-RUNX1 pathway, said Julia Hauer, MD, of Heinrich-Heine University Duesseldorf (Germany).

“The mechanism that takes place in preleukemic cells after the mice were exposed to infection was different in the two mouse models,” she said at a briefing prior to her presentation of the data at the annual congress of the European Hematology Association.

“This is another piece that will, hopefully, contribute to the picture of how exposure to infection can contribute to leukemic development” and may lead to novel approaches for leukemia prevention, she added.

The possibility that exposure to infectious pathogens could trigger leukemia has been bandied about for a century, based in part on observations that leukemia is the most common malignancy in children, with a still unexplained peak incidence between the ages of 2 and 6 years, Dr. Hauer noted.

To explore a possible link, she and her colleagues developed and characterized the aforementioned mice mimicking BCP-ALL with the BCR-ABL1 transcription and ETV6-RUNX1 BCP-ALL, in addition to a previously described Pax5+/- infection model. Some of all three mouse models were exposed not to specific pathogens but to a common laboratory environment, where they could be expected to acquire various infections at 2-3 months of age, and some were kept in a sterile environment designed to reduce transmission of pathogens. Wild-type mice were used as controls.

They observed that the Pax5+/- and ETV6-RUNX1 mice developed BCP-ALL only after exposure to common pathogens. In contrast, the BCR-ABL1p190 mice developed BCP-ALL independent of exposure to common infection.

They also determined that the mechanism leading to leukemia in the Pax5+/- mice was related to constitutive activations of mutations in the Janus kinase (JAK)3 pathway in susceptible B cell precursors, whereas the ETV6-RUNX1 mice developed BCP-ALL at a low penetrance (10.75%, 10 of 93) with a CD19-positive, B220-positive, immunoglobulin M-negative cell surface phenotype, manifested by blast cells in peripheral blood and a clonal immature B-cell receptor rearrangement.

In mice, norovirus and hepatitis C virus may be some of the pathogens most closely linked to risk of leukemia, but it’s likely that other viruses and parasitic infections will turn out to be the culprits in humans, Dr. Hauer said.

The findings raise the possibility of an unexpected link between leukemia and the so-called “hygiene hypothesis” linking childhood asthma, allergies, and atopic skin conditions to a lack of early exposure to a multiplicity of pathogens. In many developed countries, children are relatively protected from exposure to many different pathogens and may not encounter infectious agents until entering preschool or kindergarten, Dr. Hauer commented.

The study was supported by German Cancer Aid, the Jose Carreras Leukemia Foundation, and other charitable agencies. Dr. Hauer reported no relevant disclosures.

[email protected]

 

MADRID – The evidence thus far comes only from animal models, but commonly encountered childhood infections may be able to trigger the development of leukemia in those children with certain genetic predispositions to B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

Mice genetically modified to mimic BCP-ALL susceptibility and its most common subtype (ETV6-RUNX1 BCP-ALL) developed leukemia only after exposure to a common infectious environment.

The findings suggest that common pathogens could trigger childhood BCP-ALL in children with genetic mutations that lead to the loss of function of the Pax5 tumor suppressor gene or to a common translocation in the ETV6-RUNX1 pathway, said Julia Hauer, MD, of Heinrich-Heine University Duesseldorf (Germany).

“The mechanism that takes place in preleukemic cells after the mice were exposed to infection was different in the two mouse models,” she said at a briefing prior to her presentation of the data at the annual congress of the European Hematology Association.

“This is another piece that will, hopefully, contribute to the picture of how exposure to infection can contribute to leukemic development” and may lead to novel approaches for leukemia prevention, she added.

The possibility that exposure to infectious pathogens could trigger leukemia has been bandied about for a century, based in part on observations that leukemia is the most common malignancy in children, with a still unexplained peak incidence between the ages of 2 and 6 years, Dr. Hauer noted.

To explore a possible link, she and her colleagues developed and characterized the aforementioned mice mimicking BCP-ALL with the BCR-ABL1 transcription and ETV6-RUNX1 BCP-ALL, in addition to a previously described Pax5+/- infection model. Some of all three mouse models were exposed not to specific pathogens but to a common laboratory environment, where they could be expected to acquire various infections at 2-3 months of age, and some were kept in a sterile environment designed to reduce transmission of pathogens. Wild-type mice were used as controls.

They observed that the Pax5+/- and ETV6-RUNX1 mice developed BCP-ALL only after exposure to common pathogens. In contrast, the BCR-ABL1p190 mice developed BCP-ALL independent of exposure to common infection.

They also determined that the mechanism leading to leukemia in the Pax5+/- mice was related to constitutive activations of mutations in the Janus kinase (JAK)3 pathway in susceptible B cell precursors, whereas the ETV6-RUNX1 mice developed BCP-ALL at a low penetrance (10.75%, 10 of 93) with a CD19-positive, B220-positive, immunoglobulin M-negative cell surface phenotype, manifested by blast cells in peripheral blood and a clonal immature B-cell receptor rearrangement.

In mice, norovirus and hepatitis C virus may be some of the pathogens most closely linked to risk of leukemia, but it’s likely that other viruses and parasitic infections will turn out to be the culprits in humans, Dr. Hauer said.

The findings raise the possibility of an unexpected link between leukemia and the so-called “hygiene hypothesis” linking childhood asthma, allergies, and atopic skin conditions to a lack of early exposure to a multiplicity of pathogens. In many developed countries, children are relatively protected from exposure to many different pathogens and may not encounter infectious agents until entering preschool or kindergarten, Dr. Hauer commented.

The study was supported by German Cancer Aid, the Jose Carreras Leukemia Foundation, and other charitable agencies. Dr. Hauer reported no relevant disclosures.

[email protected]