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Santiago et al. J Transl Genet Genom 2021;5:380-95 https://dx.doi.org/10.20517/jtgg.2021.16 Page 384

PAX5-driven subtypes
Aberrations involving the transcription factor PAX5 has recently been individualized as a founding event in
B-lymphoid leukemogenesis [11,31] . Two distinct subgroups have been identified within PAX5-driven
mutations: PAX5 altered (PAX5alt) ALL, that comprises a diverse spectrum of PAX5 rearrangement,
intragenic amplification or sequence mutation, and PAX5 P80R. The latter is characterized by the
deleterious PAX5 P80R point mutation coexisting with a near systematic inactivation of the wild-type PAX5
allele either by deletion, loss-of-function mutation or loss of heterozygosity. Frequent signaling pathway
mutations arise concomitantly with the PAX5 P80R subtype, mostly involving RAS and JAK-STAT
pathways . The PAX5alt subtype predominates in childhood ALL (10%) compared to adult ALL (7%) and
[11]
[31]
is associated with intermediate prognosis . In contrast, PAX5 P80R increases in frequency with age and
[11]
also confers an intermediate prognosis .

MEF2D and ZNF384 rearrangements
The identification of recurrent fusions involving MEF2D and ZNF384 highly suggests their role as
oncogenic drivers in B-ALL. Both MEF2D and ZNF384-rearranged (MEF2Dr and ZNF384r) ALL harbor a
profile of activated transcription factor gene and disruption in B-cell development, but still present a
distinct GEP allowing for the definition of two new subgroups [31,32] . MEFD2r and ZNF384r resemble by their
multiple fusion partners, the most common being BCL9 for the former and EP300 for the latter [33,34] . These
rare subsets are found in adolescents and young adults (AYA) more often than in younger children, each
subset totaling roughly 7% of B-ALL in AYA and 4% in children [32,34] . The scarcity of these subgroups lessens
the ability to accurately determine their prognostic significance; however, MEFD2 fusions appear to confer a
poor prognosis, while ZNF384 fusions are associated with an intermediate prognosis [31,32] . Interestingly, their
molecular signatures are characterized by distinct immunophenotypes. MEF2Dr ALL tends to lack CD10
surface marker while expressing CD38; whereas ZNF384r ALL exhibits lineage plasticity and may be found
in approximately half of B/myeloid mixed-phenotype acute leukemia (MPAL) with frequent co-expression
of myeloid markers (CD13 and CD33) and lack of CD10 expression [33,34] . Considering the lineage aberrancy
in a patient with MPAL, ZNF384 fusion may represent a more reliable diagnostic biomarker rather than
relying on the immunophenotype [9,35] .

Rare newly defined subgroups
Most recently, two different teams have described novel rare subgroups, totaling up to 23 B-ALL
subtypes [11,31] . The rarity of these subsets yields uncertain prognostic interpretation that will require further
validation. First, fusions in the chromatin regulator NUTM1, described in about 1% of B-ALL, harbor a
unique transcriptional signature and enriched among KMT2A-germline infant ALL cases . Secondly, while
[36]
IKZF1 alterations can be encountered across different molecular subgroups in B-ALL, the missense
mutation IKZF1 N159Y reveals a strikingly distinct molecular signature. Finally, despite recurrent IGH
rearrangements to multiple partners are often encountered in B-ALL, the rearrangement of IGH to BCL2,
MYC and/or BCL6 defines a new subgroup that is present mostly in adult ALL, accounting for 1% of
them [11,31] . Thus, the advent of NGS, in particular with the increasing utilization of whole transcriptome
analysis or other clinical RNA-based fusion assays, now enables molecular profiling and classification for
approximately 95% of all pediatric B-ALL [9,27] . However, it is important to recognize that the prognostic
significance of these rare molecular subgroups is limited by the paucity of cases and should be confirmed in
large, prospective, multicenter clinical trials. It is unknown whether the prognostic impact of these gene
alterations remains independently adverse in the context of modern MRD-directed treatment strategies.

T-lineage ALL
T-cell ALL (T-ALL) represents 15% of pediatric ALL and up to 25% of adult ALL [2,37] . Its prognosis is
historically considered inferior to that of B-ALL and remains a HR determinant in several ALL protocols.