Human NUP98-HOXA9 promotes hyperplastic growth of hematopoietic tissues in Drosophila

Abstract

Acute myeloid leukemia (AML) is a complex malignancy with poor prognosis. Several genetic lesions can lead to the disease. One of these corresponds to the NUP98-HOXA9 (NA9) translocation that fuses sequences encoding the N-terminal part of NUP98 to those encoding the DNA-binding domain of HOXA9. Despite several studies, the mechanism underlying NA9 ability to induce leukemia is still unclear. To bridge this gap, we sought to functionally dissect NA9 activity using Drosophila. For this, we generated transgenic NA9 fly lines and expressed the oncoprotein during larval hematopoiesis. This markedly enhanced cell proliferation and tissue growth, but did not alter cell fate specification. Moreover, reminiscent to NA9 activity in mammals, strong cooperation was observed between NA9 and the MEIS homolog HTH. Genetic characterization of NA9-induced phenotypes suggested interference with PVR (Flt1-4 RTK homolog) signaling, which is similar to functional interactions observed in mammals between Flt3 and HOXA9 in leukemia. Finally, NA9 expression was also found to induce non-cell autonomous effects, raising the possibility that its leukemia-inducing activity also relies on this property. Together, our work suggests that NA9 ability to induce blood cell expansion is evolutionarily conserved. The amenability of NA9 activity to a genetically-tractable system should facilitate unraveling its molecular underpinnings.

A genetic screen in Drosophila uncovers the multifaceted properties of the NUP98-HOXA9 oncogene

“…A variety of models have been used to characterize the molecular and cellular events underlying the leukemogenic activity of NA9 [26,28,35,36]. For example, we have recently shown that expression of human NA9 in the hematopoietic organ of Drosophila larvae, called the lymph gland, triggers the premature differentiation of hemocyte progenitors followed by their proliferation [35].…”

Turning Stem Cells Bad: Generation of Clinically Relevant Models of Human Acute Myeloid Leukemia through Gene Delivery- or Genome Editing-Based Approaches

“…These findings nicely dovetailed with the data reported at the same time by Levine et al [ 32 ], who detected in the great majority of myeloproliferative syndromes-and in particular in almost all cases of polycythemia vera-a V617F mutation occurring in the coding sequence of the Janus kinase 2 (JAK2) that constitutively activated this receptor-associated tyrosine kinase, resulting in turn in the strong activation of STAT5. Subsequent investigations confirmed the results of these studies and provided additional insights into the biological effects and the mechanism of action of constitutively-active FLT3-ITD and STAT5a, as well as of the NUP98-HOXA9 fusion protein in normal and malignant hematopoietic stem and progenitor cells [ 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ].…”

Mis-regulation of the Nucleoporins 98 and 96 lead to defects in protein synthesis that promote hallmarks of tumorigenesis

“…It is possible effects of Nup98 mis-regulation impact different tissue types through similar pathways, but with distinct outcomes. For example, expression of a NUP98-HOXA9 fusion in a Drosophila model with a normal Nup98-96 locus leads to hyperplastic over-proliferation in hematopoietic tissues but minimal effects in epithelial tissues (Baril et al, 2017), while loss of Nup98-96 in larval hematopoietic tissues leads to a loss of progenitors, a phenotype also observed upon inhibition of the ribosomal protein RpS8 (Mondal et al, 2014). Thus Nup98-96 loss likely has distinct yet overlapping effects in different tissue types.…”