Oral Presentation Indian Ocean Rim Laboratory Haematology Congress 2019

GATA-1 overexpression promotes megakaryocyte hyperplasia in myeloproliferative neoplasms (#48)

Aidan D Yuen-Oye 1 , Jacques AJ Malherbe 2 , Kathryn A Fuller 2 3 , Bob Mirzai 2 3 , Belinda B Guo 2 , Wendy N Erber 1 2 3
  1. Medical School, University of Western Australia, Perth, WA, Australia
  2. School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia
  3. PathWest Laboratory Medicine, Perth, WA, Australia

Background & Aims: Myeloproliferative neoplasms (MPN) are chronic, haematological disorders characterised by megakaryocyte hyperplasia and atypia. Transformation to myelofibrosis (MF) is associated with poor prognosis, but it is unclear what drives this progression. Deficiency of GATA-1, a key transcription factor which regulates megakaryopoiesis, has been shown in murine models to promote megakaryocyte production with paradoxical thrombocytopaenia and MF. There is little data pertaining to GATA-1 expression in human megakaryocytes and its role in MPN pathobiology. We investigated the expression of GATA-1 in megakaryocytes of MPN patients and its potential association with transformation to MF.

Methods: GATA-1 expression in megakaryocytes was evaluated in bone marrow trephine biopsy specimens of MPN (n=92) and non-MPN controls (n=39) using immunohistochemistry. The percent megakaryocytes positive for GATA-1 was assessed by light microscopy. Comparisons were made between MPN and controls, by MPN subtype (i.e. polycythaemia vera (PV), essential thrombocythaemia (ET) and MF) and mutation profiles (i.e. JAK2V617F, CALR­-mutated and double-negative). GATA-1 expression was also correlated with platelet count.

Results: The mean percent GATA-1 positive megakaryocytes in MPN (76.1±11.1%) was significantly higher than controls (67.6±13.7%, p<0.0001). There was no significant difference between MPN subtypes i.e. PV=74.4±11.3%, ET=76.6±11.7%, MF=76.4±10.7%, or between driver mutations (JAK2V617F 76.2±11.5%; CALR-mutated 74.8±14.3% and double-negatives 74.9±8.6%). There was a weak correlation between GATA-1 positivity and platelet count, r=0.21, p=0.01.

Conclusions: GATA-1 is upregulated in megakaryocytes of MPN patients, irrespective of the underlying disease phenotype or mutation status. Its expression also correlates with platelet production. This suggests that GATA-1 overexpression promotes megakaryocytic hyperplasia and is associated with thrombocytosis in MPN. However, it is unlikely to have a direct role in MF transformation. Nevertheless, its overexpression in human megakaryocytes may facilitate the development of an MPN and represents a potential therapeutic target.