GATA1 Insufficiencies in Dysmegakaryopoiesis of Myelodysplastic Syndromes/Neoplasms

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Introduction: GATA1 is one of critical transcription factors for megakaryopoiesis and platelet production. Our study aimed to explore the correlations between GATA1 expression and dysmegakaryopoiesis in myelodysplastic syndromes/neoplasm (MDS). Methods: Data of blood cell counts, cytogenetics and next-generation sequencing from 90 MDS patients at diagnosis were collected. Firstly, we assessed GATA1 expression level of megakaryocytes by performing immunohistochemical staining on bone marrow biopsy sections from the aforementioned 90 MDS patients. According to GATA1 expression level of megakaryocytes and positive megakaryocyte percentage, we assigned each patient a GATA1 score. Furthermore, we explored the correlation between GATA1 expression levels and cytogenetic abnormalities of the same megakaryocytes using the morphology antibody chromosome (MAC) technique on fresh bone marrow smears from another 6 MDS patients. To explore the significance of GATA1 expression levels in the prognosis of MDS, we included GATA1 scores in a multivariable analysis of overall survival (OS). Results: Patients with abnormal karyotypes showed decreased GATA1 scores than those with normal karyotypes (6.0 [3.0-10.5] versus 12.0 [4.0-12.0] scores, P = 0.024). Compared with TP53-wildtype patients, GATA1 scores significantly decreased in TP53-mutated patients (3.0 [2.3-6.0] versus 12.0 [6.5-12.0] scores, P < 0.001). However, patients with mutations of other genes showed no significant differences in GATA1 scores compared with wildtype patients (P > 0.05). GATA1 expression levels were significantly downregulated in dysplastic megakaryocytes, especially micromegakaryocytes (P < 0.001). Furthermore, we found that GATA1-negative megakaryocytes had higher frequencies of cytogenetic abnormalities (87.5% versus 47.6%, P = 0.002) using MAC technique. The multivariable analysis of overall survival that lower GATA1 scores (P = 0.005) were significantly associated with inferior OS in MDS, independent of the IPSS-R higher-risk category (IPSS-R scores > 3.5 points). Conclusion: Our results indicated that decreased GATA1 expression level of megakaryocytes was significantly associated with TP53 mutations, abnormal karyotypes and dysmegakaryopoiesis in MDS, suggesting that downregulation of GATA1 expression levels of megakaryocytes plays a critical role in the pathogenesis of MDS.

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