GATA1 mutation analysis and molecular landscape characterization in acute myeloid leukemia with trisomy 21 in pediatric patients

Abstract

Introduction Accurate detection of GATA1 mutation is highly significant in patients with acute myeloid leukemia (AML) and trisomy 21 as it allows optimization of clinical protocol. This study was aimed at (a) enhanced search for GATA1 mutations; and (b) characterization of molecular landscapes for such conditions. Methods The DNA samples from 44 patients with newly diagnosed de novo AML with trisomy 21 were examined by fragment analysis and Sanger sequencing of the GATA1 exon 2, complemented by targeted high‐throughput sequencing (HTS). Results Acquired GATA1 mutations were identified in 43 cases (98%). Additional mutations in the genes of JAK/STAT signaling, cohesin complex, and RAS pathway activation were revealed by HTS in 48%, 36%, and 16% of the cases, respectively. Conclusions The GATA1 mutations were reliably determined by fragment analysis and/or Sanger sequencing in a single PCR amplicon manner. For patients with extremely low blast counts and/or rare variants, the rapid screening with simple molecular approaches must be complemented with HTS. The JAK/STAT and RAS pathway‐activating mutations may represent an extra option of targeted therapy with kinase inhibitors.

Advances in molecular characterization of myeloid proliferations associated with Down syndrome

“…Because blasts are the cells that carry GATA1s in ML-DS, their paucity may limit detection. Similar to DS-like TAM, ML-DS-like leukaemia may arise in children without DS where GATA1s and trisomy 21 are somatically acquired in leukemic blasts ( Ono et al, 2015 ; De Rooij et al, 2017 ; Panferova et al, 2021 ), or GATA1s mutations may be germline ( Hasle et al, 2022 ). ML-DS-like leukemia is very rare but it shares multiple pathologic and clinical features with ML-DS, including good prognosis ( De Rooij et al, 2017 ), emphasizing the importance of recognizing ML-DS-like leukemia in non-DS children.…”

“…It has become well accepted that evolution from TAM to ML-DS relies on the acquisition of tertiary somatic mutations and additional chromosomal structural aberrations in GATA1s -mutated cells. Tertiary mutations seen in ML-DS most commonly affect genes encoding the cohesin complex, JAK family kinases, and epigenetic regulators; other mutations occur in genes recurrently mutated in other types of AML, including fms-like tyrosine kinase 3 ( FLT3 ) and TP53 ( Table 2 ) ( Yoshida et al, 2013 ; Labuhn et al, 2019 ; Panferova et al, 2021 ). Patients with TAM usually harbor fewer tertiary mutations than those with ML-DS, at the average of 0.4 and 1.6 variants per sample respectively ( Labuhn et al, 2019 ).…”

“…Mutations in RAS (Rat sarcoma virus) gene family members, such as KRAS , NF1 , NRAS , and PTPN11, are found in 14% of ML-DS samples ( Labuhn et al, 2019 ). NRAS and KRAS variants are the most common accounting for 4.5–8.2% and 4.3–9.1% of ML-DS cases respectively ( Yoshida et al, 2013 ; Labuhn et al, 2019 ; Panferova et al, 2021 ). Ras belongs to the small GTPase family that binds to guanosine triphosphate (GTP) and hydrolyses it to guanosine diphosphate (GDP), with three distinct isoforms NRas, KRas, and HRas ( Padmakumar et al, 2021 ).…”

“…TAM is extremely rare in neonates without DS but such cases have been well documented ( Apollonsky et al, 2008 ; Tsai et al, 2011 ; Ono et al, 2015 ; Yuzawa et al, 2020 ; Panferova et al, 2021 ). The molecular pathogenesis and clinical outcomes of TAM in neonates without DS are similar to those with DS (i.e., DS-like).…”

“…Rare cases of TAM without GATA1 mutations feature in the literature. However, this may be due to technical limitations, in particular prior to the use of sensitive next-generation-sequencing methods ( Panferova et al, 2021 ), small disease clones, or the lack of appropriate diagnostic samples if the condition is not suspected at presentation ( Aksu et al, 2020 ). The expanding use of sensitive sequencing technologies will make the diagnosis of DS-like TAM easier in the future, which should advance our knowledge about this extremely rare condition.…”