Sustained fetal hematopoiesis causes juvenile death from leukemia: Evidence from a dual-age-specific mouse model

Nitza Vara, Yuqing Liu, Yan Yan, Shelly Y. Lensing, Natalia Colorado, Delli Robinson, Jingliao Zhang, Xin Zhang, Erich A. Peterson, Nicholas J. Baltz, Daohong Zhou, Alice Bertaina, Donald J. Johann, Peter D. Emanuel, Y. Lucy Liu

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

It is not clear whether disrupted age-specific hematopoiesis contributes to the complex manifestations in leukemia patients who carry identical mutations, particularly in pediatric and adult patients with similar clinical characteristics. By studying a dual-age-specific mouse model, we demonstrate that (1) loss of Pten during the fetal-to-adult hematopoiesis switch (hematopoiesis switch) causes sustained fetal hematopoiesis, resulting in death in juvenile leukemia; (2) myeloid-biased hematopoiesis in juvenile mice is associated with the sustained fetal properties of hematopoietic stem cells (HSCs); (3) the age specificity of juvenile myelomonocytic leukemia depends on the copy number of Pten and Nf1; (4) singleallelic Pten deletion during the hematopoiesis switch causes constitutive activation of MAPK in juvenile mice with Nf1 loss of heterozygosity (LOH); and (5) Nf1 LOH causes monocytosis in juvenile mice with Pten haploinsufficiency but does not cause lethality until adulthood. Our data suggest that 1 copy of Pten is sufficient to maintain an intact negative-feedback loop of the Akt pathway and HSC function in reconstitution, despite MAPK being constitutively activated in juvenile Pten+/Δ Nf1LOH mice. However, 2 copies of Pten are required to maintain the integrity of the MAPK pathway in juvenile mice with Nf1 haploinsufficiency. Our data indicate that previous investigations of Pten function in wild-type mice may not reflect the impact of Pten loss in mice with Nf1 mutations or other genetic defects. We provide a proof of concept that disassociated age-specific hematopoiesis contributes to leukemogenesis and pediatric demise.

Original languageEnglish (US)
Pages (from-to)3728-3740
Number of pages13
JournalBlood Advances
Volume4
Issue number15
DOIs
StatePublished - Aug 11 2020
Externally publishedYes

ASJC Scopus subject areas

  • Hematology

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