Page 42 - 2020_11-Haematologica-web

H. Inaba and C.G. Mullighan
and they account for 25% and 20%, respectively, of adult ALL. The prevalence of BCR-ABL1 ALL rises progressively from <20% of ALL in adults younger than 25 years to more than half of adults aged 50-60 years, whereas the prevalence of Ph-like ALL peaks in young adulthood, and this subtype is observed in up to 25% of adults. Alterations of B-lineage transcription factor genes, partic- ularly IKZF1, are a hallmark of BCR-ABL1 ALL18 and are a key determinant of lymphoid lineage and resistance to therapy.56 IKZF1 alterations are associated with poor out- come in ALL overall,19 particularly because of the high prevalence in BCR-ABL1 and Ph-like ALL; however, they are not associated with poor outcome in DUX4- rearranged ALL. This has led to the definition of “IKZF1- plus” as a marker of poor outcome in ALL, being defined by the presence of alterations in IKZF1 and CDKN2A/B, PAX5, or pseudoautosomal region 1 (PAR1, as a surrogate for CRLF2 rearrangement), but not ERG (as a surrogate for DUX4-rearranged ALL), commonly detected by multiplex ligation-dependent probe amplification (MLPA).58 Although used for risk-stratification in several clinical tri- als, the utility of this approach is limited by the inability of MLPA to identify all cases with key high-risk (CRLF2 rearrangement) and favorable-risk (DUX4 rearrangements) that co-occur with IKZF1 alterations.
Ph-like ALL has a similar transcriptional profile to Ph- positive ALL but is BCR-ABL1 negative.19,59 It is genetically heterogeneous with multiple rearrangements (e.g., of CRLF2, ABL-class genes, JAK-STAT signaling genes, FGFR1, and/or NTRK3), copy number alterations, and sequence mutations that activate tyrosine kinase or cytokine receptor signaling (Figure 3). Ph-like ALL is asso- ciated with elevated minimal residual disease (MRD) levels and/or high rates of treatment failure. The diverse genetic alterations characteristic of Ph-like ALL and its responsive- ness to tyrosine kinase inhibitors (at least for ABL-class and NTRK3-rearranged ALL) have spurred the use of RNA- sequencing approaches to identify such alterations at diag- nosis and direct patients to targeted therapy.36
Genetic basis of T-cell acute lymphoblastic leukemia
Childhood T-cell acute lymphoblastic leukemia is char- acterized by recurrent alterations in ten pathways, but in most cases, three pathways are deregulated: expression of T-lineage transcription factors, NOTCH1/MYC signaling, and cell-cycle control. Gene expression profiling enables classification of >90% of T-ALL into core subgroups defined by deregulation of T-ALL transcription factors as a result of rearrangement with T-cell receptor enhancers, structural variants, or enhancer mutations of TAL1, TAL2, TLX1, TLX, HOXA, LMO1/LMO2, LMO2/LYL1, or NKX2-1 (Table 2).60-62 A more recently described mecha- nism of deregulation is through small insertion/deletion mutations upstream of TAL1, which lead to a new binding motif for MYB or TCF1/TCF2 and subsequent changes in TAL1 expression.62,63 A similar mechanism has been described for other oncogenes in T-ALL, including LMO2.64 Additional transcription factor genes, including ETV6, RUNX1, and GATA3, are altered by deletion or sequence mutation but are not subtype-defining.65-67 The second core transcriptional pathway mutation found in most T-ALL cases is aberrant activation of NOTCH1, a critical transcription factor for T-cell development.68 Constitutive NOTCH1 activity, caused by activating NOTCH1 mutations (in >75% of cases) and/or inhibitor
mutations in the negative regulator FBXW7 (in 25% of cases), promotes uncontrolled cell growth, partly through increased MYC expression.69-71 The third core alteration observed in pediatric T-ALL is deletion of tumor suppres- sor loci, primarily CDKN2A/CDKN2B (in 80% of cases) and, less commonly, CDKN1B, RB1, or CCND3.62,72
In addition to the aforementioned core alterations, T- ALL frequently involves derangement of additional tran- scriptional regulators (MYB, LEF1, and BCL11B), riboso- mal function, ubiquitination through loss-of-function USP7 mutations, RNA processing, signaling pathways, and epigenetic modifiers such as PHF6, KDM6A, and genes of polycomb repressive complex 2 (EED, SUZ12, and EZH2).62 The signaling pathway most commonly acti- vated is PI3K-AKT, through loss of negative regulation by PTEN.73 JAK-STAT pathway activation can occur through gain-of-function mutations in IL7R, JAK1, JAK3, or STAT5B or through loss-of-function alterations in the JAK- STAT regulators PTPN2 and SH2B3,74,75 whereas muta- tions in RAS-MAPK signaling are less common, except in early T-cell precursor (ETP) ALL. Kinase rearrangements are observed in a minority of cases, particularly the NUP214-ABL1 rearrangement.76
Genetics of relapse
The subclonal complexity of ALL is now well estab- lished, and the clonal dynamics during therapy and at relapse have been examined through genomic sequencing and single-cell analysis.77,78 Chimeric fusions, when present, are often clonal leukemia-initiating lesions that are typically retained throughout disease progression. Alterations of sig- naling pathway lesions (FLT3, KRAS, NRAS) are often sub- clonal and are frequently lost or gained between diagnosis and relapse.79
In B-ALL, mutations in genes such as the histone acetyl transferase gene CREBBP, the histone methyltransferase gene SETD2, and the steroid receptor genes NR3C1 and NR3C2 are enriched at relapse.80-83 At diagnosis, minor relapse-initiating subclones can exhibit inherent resistance to chemotherapy, even before secondary mutation acquisi- tion.84 Other relapse-specific mutations in PRPS1, PRSP2, NT5C2, or MSH6, each influencing thiopurine metabolism, may emerge only during therapy, being driven by selective therapeutic pressure.81,83,85,86 These mutations confer chemotherapy resistance and might have implications for disease monitoring and therapeutic decisions.85,86 Inherited genomic variants in specific ethnic/racial groups also con- tribute to relapse risk as a result of differential drug metab- olism or acquisition of distinct somatic mutations.87-89 Monitoring the dynamics of mutation clearance during induction therapy or monitoring for the emergence of relapse-associated mutations might identify patients who will benefit from early modification of therapy.
Mixed-phenotype acute leukemia
Mixed-phenotype acute leukemia (MPAL) is uncom- mon, representing only 2-5% of pediatric acute leukemia.48 The 2016 World Health Organization (WHO) classification defines MPAL as acute leukemia expressing a combination of antigens not restricted to a single lineage with the following categories: B/myeloid, not otherwise specified (NOS) and T/myeloid, NOS, in addition to two genetic subgroups of MPAL: that with t(9;22)(q34.1;q11.2), BCR-ABL1; and that with t(v;11q23.3), KMT2A-rearranged.90 Genetic characteriza-
2530
haematologica | 2020; 105(11)