Acute myeloid leukemia with t(X;6)9p11;q23);MYB-GATA1 and female sex: GATA1 insufficiency may be insufficient for pathogenesis.

Pediatric acute myeloid leukemia (AML) is genetically heterogenous (Olsson et al., 2016). t(X;6)(p11;q23) is a rare but recurrent chromosomal translocation in infant AML thought to be associated with male sex and basophilic differentiation (Dastugue et al., 1997). Here we report molecular characterization of AML with t(X;6)(p11;q23);MYB-GATA1 in two female infants and demonstrate preserved GATA1 expression in the sample tested. These findings further debunk a concept that this fusion was restricted to males, in whom it disrupts the only copy of the X-linked GATA1 gene, causing presumable complete loss of GATA1 function. Our data also demonstrate the power and efficiency of RNA sequencing for subclassification of leukemia on a clinically relevant timeline.

Quantification of NG2-positivity for the precise prediction of KMT2A gene rearrangements in childhood acute leukemia.

It has long been known that there is a link between neuron glial antigen 2 (NG2) surface expression and KMT2A gene rearrangements in acute leukemia (AL). However, the exact levels of NG2 positivity that predict the presence of KMT2A rearrangement are not known. The current study focuses on a cohort of 505 pediatric AL patients who showed any level of positive NG2 expression (greater than 1% of cells) for whom comprehensive genetic data were available. NG2 expression was measured as either the percentage of positive cells or the number of molecules on the cell surface. KMT2A gene rearrangements were identified by FISH. The fusion partner was detected with RT-PCR, LDI-PCR or anchored multiplex PCR followed by high-throughput sequencing. KMT2A-positive samples comprised a substantial proportion of the NG2-positive cohort (180 of 505, 36%), with a total of 19 different types of translocation. Despite its occurrence in other AL genetic subgroups, NG2 expression was significantly increased in AL patients with KMT2A rearrangements in terms of both the cell percentage and number of molecules per cell. The threshold levels (TL) for NG2-positivity were established by ROC analysis of the whole cohort and separately for children less than 1 years old and older with lymphoblastic (ALL) and myeloid (AML) leukemia. The lowest TL was defined in infants with ALL (7%), while in older children, the threshold was higher (12%). In AML patients, the situation was reversed, with 28% NG2-positivity in infants and 14% in patients >1 year old. The defined TLs resulted in improved diagnostic performance compared to the conventional thresholds of 10% and 20% for all patient groups.