Page 40 - 2020_11-Haematologica-web

H. Inaba and C.G. Mullighan
scription factors and are rearranged with genes encoding N-terminal transcription factors (e.g., TAF15 and TCF3) or chromatin modifiers (most commonly EP300, but also CREBBP, SMARCA2, and ARID1B).47 ZNF384-rearranged leukemia is associated with elevated FLT3 expression, and there are anecdotal reports of profound responses to FLT3 inhibition.49 The lineage-ambiguous phenotype of ZNF384-rearranged leukemia may shift during the dis- ease course and may result in loss of CD19 expression and failure of chimeric antigen receptor T-cell therapy.50
MEF2D (myocyte enhancer factor 2D)-rearranged ALL (occurring in 4% of children and up to 10% of adults with ALL) has a distinct immunophenotype (CD10−, CD38+), an older age of diagnosis (median: 14-15 years), and a poor prognosis.51-53 The rearrangements result in increased HDAC9 expression and sensitivity to histone deacetylase inhibitor treatment.51
NUTM1 (nuclear protein in testis midline carcinoma family 1) rearrangements are observed in 1-2% of child- hood B-ALL, with fusion to genes encoding various tran- scription factors and epigenetic regulators (e.g., ACIN1, BRD9, CUX1, IKZF1, SLC12A6, and ZNF618) that drive aberrant NUTM1 expression.15,47 In all fusions, the NUT domain is retained, and this is hypothesized to lead to global changes in chromatin acetylation and to sensitivity to histone deacetylase inhibitors or bromodomain inhibitors. ALL with NUTM1 rearrangements has an excellent prognosis.
Other transcription factor-driven subtypes of B-cell acute lymphoblastic leukemia
Two B-ALL subtypes have distinct alterations of the lymphoid transcription factor PAX5. PAX5-altered (PAX5alt) B-ALL accounts for 10% of childhood B-ALL, with cases featuring diverse PAX5 alterations, including rearrangements (most commonly with ETV6 or NOL4L), sequence mutations or intragenic amplification,54 and an intermediate prognosis.15,47 PAX5 P80R B-ALL accounts for approximately 2% of childhood B-ALL, with cases featur- ing universal P80R mutation and deletion/mutation of the remaining allele,15,47,55 mutations in Ras and JAK2 signaling genes, and an intermediate to favorable prognosis.15,55 A single heterozygous mutation in IKZF1 (N159Y) defines a novel subtype of ALL (representing <1% of cases) with IKZF1 nuclear mislocalization, enhanced intercellular adhesion,56 and expression of genes involved in oncogen- esis (YAP1), chromatin remodeling (SALL1), and JAK- STAT signaling.15,47 The IGH-CEBPE fusion and ZEB2 H1038R mutation are common, but not universal, events in a transcriptionally distinct form of leukemia observed in approximately 1% of cases.
Kinase-driven subtypes
Of therapeutic relevance are the two kinase-driven sub- types: Philadelphia chromosome-positive (Ph+ or BCR- ABL1+) and Philadelphia chromosome-like (Ph-like or BCR-ABL1-like) ALL. Their frequency increases with age,57
Figure 2. Distribution of B-cell acute lymphoblastic leukemia (B-ALL) subtypes within each age group. SR: standard risk; HR: high risk; WBC: white blood cell count; AYA: adolescent and young adult.
2528
haematologica | 2020; 105(11)