Developmental stage-specific interplay of GATA1 and IGF signaling in fetal megakaryopoiesis and leukemogenesis

Abstract

Oncogene-mediated transformation of hematopoietic cells has been studied extensively, but little is known about the molecular basis for restriction of oncogenes to certain target cells and differential cellular context-specific requirements for oncogenic transformation between infant and adult leukemias. Understanding cell type-specific interplay of signaling pathways and oncogenes is essential for developing targeted cancer therapies. Here, we address the vexing issue of how developmental restriction is achieved in Down syndrome acute megakaryoblastic leukemia (DS-AMKL), characterized by the triad of fetal origin, mutated GATA1 (GATA1s), and trisomy 21. We demonstrate overactivity of insulin-like growth factor (IGF) signaling in authentic human DS-AMKL and in a DS-AMKL mouse model generated through retroviral insertional mutagenesis. Fetal but not adult megakaryocytic progenitors are dependent on this pathway. GATA1 restricts IGF-mediated activation of the E2F transcription network to coordinate proliferation and differentiation. Failure of a direct GATA1-E2F interaction in mutated GATA1s converges with overactive IGF signaling to promote cellular transformation of DS fetal progenitors, revealing a complex, fetal stage-specific regulatory network. Our study underscores context-dependent requirements during oncogenesis, and explains resistance to transformation of ostensibly similar adult progenitors.[Keywords: DS-AMKL; Down syndrome; GATA1; IGF signaling; IGF1R; megakaryoblastic leukemia] Supplemental material is available at http://www.genesdev.org.

Pluripotent stem cells reveal erythroid-specific activities of the GATA1 N-terminus

“…In addition, we show that GATA1s enhances human megakaryocyte and myeloid expansion, which likely contributes to the development of DS-associated myeloproliferative disorders. A LXCXE motif within the N-terminus of GATA1 (amino acids 81-85) binds Rb-E2F transcription factor family members, which inhibits the expression of genes that stimulate cell proliferation (56,65). Studies of GATA1 alleles in DS-TMD patients, including rare cases with mutations that produce internal protein deletions (66), map a minimal disease-associated domain to within amino acids 74-83, which includes the Rb-binding motif.…”

Global transcriptome and chromatin occupancy analysis reveal the short isoform of GATA1 is deficient for erythroid specification and gene expression

“…47 Loss of the Rb interaction is also thought to contribute to leukemic transformation in DS-AMKL through increased E2F activity. 48 It is possible that there are multiple factors that contribute to the erythroid specific deficiency caused by GATA1s mutations. A promising candidate is LMO2, a component of the SCL pentameric complex, which is known to co-operate with GATA1 in gene activation but not gene repression.…”

miR-99a/100∼125b tricistrons regulate hematopoietic stem and progenitor cell homeostasis by shifting the balance between TGFβ and Wnt signaling

“…FL CD34 + HSPCs were purchased from Novogenic Laboratories. Culture conditions for maintenance, megakaryocytic, or megakaryocytic/erythroid in vitro differentiation of CD34 + HSPCs were described elsewhere (Klusmann et al 2010a;Kumar et al 2011;Emmrich et al 2012;Stankov et al 2014). Cell lines (CMK, K562, MV4:11, THP-1, and NB4) were purchased from the German National Resource Center for Biological Material (DSMZ) and maintained under recommended conditions.…”