Mutational profile of ZBTB16‐RARA‐positive acute myeloid leukemia

Abstract

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Natural history of Ras‐associated autoimmune leukoproliferative disorder: A 20‐year follow‐up of a NRAS‐mutated patient excluding a malignant progression

“…Targeted deep sequencing was studied at two different time points (at age of 13 and 20 years) on DNA extracted from PBMCs using the 30-gene myeloid solution panel by Sophia Genetics. 6 The NRAS mutation was confirmed with a stable variant allele frequency at first and second determination, 0.48 and 0.50 respectively, without any other somatic mutations.…”

“…9 In RALD, immunological alterations, as well as decreased naïve lymphocytes, the peripheral oligoclonal T-and B-cell expansion 10 and the intrinsic apoptotic defect 9 could contribute to a large spectrum of clinical and immunological manifestations (Figure 1). 1,6,11 JMML is a rare aggressive myelodysplastic/myeloproliferative disorder of early childhood that shares clinical features with RALD. In 90% of JMML, a GoF somatic mutation in NRAS, KRAS or PTPN11 is identified, or diagnosed in the context of RASopathies (germline mutations in RAS/MAPK pathway genes as NF1 and CBL).…”

Atypical Rearrangements in APL-Like Acute Myeloid Leukemias: Molecular Characterization and Prognosis

“…In contrast to classic APL ( 109 , 110 ), characterized by a low number of additional mutations, this variant presents a complex molecular landscape, similar to other acute myeloid leukemias (AML) ( 109 , 110 ). Our group showed that ZBTB16-RARA rearranged AML and display several gene mutations commonly identified in AML, including TET2 , RUNX1 , and CSF3R , and in particular, the most frequent alteration was found in the AT-rich interacting domain containing protein 1A gene ( AIRD1A , in 6 out of 7 patients analyzed), a member of the SWI/SNF family of transcriptional regulators, which is a known solid and hematological cancer development driver ( 26 , 111 ).…”

“…Data in literature report a lower incidence of coagulopathy compared to classic APL (40–55%) and a poor outcome, with less than half of the patients surviving at prolonged follow-up ( 26 – 28 , 102 ). The therapy with ATRA and ATO is not effective on ZBTB16-RARA AML, and the resistance to ATO is due to the lack of an ATO-binding site, whereas although ATRA induces the degradation of the fusion protein, differentiation and apoptosis do not occur, and there is no clinical response.…”

“…The pathogenesis of APL has been extensively studied and discussed in previous papers. The chromosomal translocation t(15;17), resulting in the PML-RARA fusion protein, is the main and, probably, the only driver alteration of APL, where additional gene mutations have been reported at a significantly lower rate when compared to other AML subtypes ( 26 , 104 , 105 ). The differentiation block typical of APL results from the destruction of PML nuclear bodies, implicated in DNA replication, transcription, and epigenetic silencing, and from the repression of RARA target differentiation genes by the aberrant recruitment of histone deacetylases ( 2 – 4 , 105 , 106 ).…”