Choorapoikayil, S., Kers, R., Herbomel, P., Kissa, K., and den Hertog, J. (2014) Pivotal role of Pten in the balance between proliferation and differentiation of hematopoietic stem cells in zebrafish. Blood. .
Self-renewing hematopoietic stem/progenitor cells (HSPCs) produce blood cells of all lineages throughout life. PTEN, a tumor
suppressor that antagonizes PI3-Kinase (PI3K) signaling, is frequently mutated in hematologic malignancies such as bone marrow
failure and leukemia. We set out to investigate if Pten is required for hematopoiesis. Analysis of zebrafish mutants lacking
functional Pten revealed that HSPCs colonized the caudal hematopoietic tissue (CHT) normally. There, HSPCs hyperproliferated
and engaged in all blood lineages. However, they failed to differentiate into mature blood cells. Hence, Pten mutant zebrafish
embryos displayed hallmarks of leukemia in humans. Inhibition of PI3K signaling in mutants lacking functional Pten suppressed
hyperproliferation and released the differentiation arrest. We conclude that Pten has an essential role in the balance between
proliferation and differentiation of blood cells.