Emerging molecular subtypes and therapeutic targets in B-cell precursor acute lymphoblastic leukemia

Abstract

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is characterized by genetic alterations with high heterogeneity. Precise subtypes with distinct genomic and/or gene expression patterns have been recently revealed using high-throughput sequencing technology. Most of these profiles are associated with recurrent non-overlapping rearrangements or hotspot point mutations that are analogous to the established subtypes, such as DUX4 rearrangements, MEF2D rearrangements, ZNF384/ZNF362 rearrangements, NUTM1 rearrangements, BCL2/MYC and/or BCL6 rearrangements, ETV6-RUNX1-like gene expression, PAX5alt (diverse PAX5 alterations, including rearrangements, intragenic amplifications, or mutations), and hotspot mutations PAX5 (p.Pro80Arg) with biallelic PAX5 alterations, IKZF1 (p.Asn159Tyr), and ZEB2 (p.His1038Arg). These molecular subtypes could be classified by gene expression patterns with RNA-seq technology. Refined molecular classification greatly improved the treatment strategy. Multiagent therapy regimens, including target inhibitors (e.g., imatinib), immunomodulators, monoclonal antibodies, and chimeric antigen receptor T-cell (CAR-T) therapy, are transforming the clinical practice from chemotherapy drugs to personalized medicine in the field of risk-directed disease management. We provide an update on our knowledge of emerging molecular subtypes and therapeutic targets in BCP-ALL.

Biologic and Therapeutic Implications of Genomic Alterations in Acute Lymphoblastic Leukemia

“…In unsupervised clustering of leukemic cell gene expression, cases with the H1038R mutation in ZEB2 phenocopy the translocation t(14;14)(q11;q32) [13], which results in IGH-CEBPE fusion, suggesting a common activated pathway of leukemogenesis and defining a rare B-ALL subtype (<1%). This is associated with NRAS sequence mutations (>50% of cases), upregulation of LMO1 and downregulation of SMAD1 and BMP2 [10]. However, neither the IGH or ZEB2 mutations are unique to this group, nor do they explain all cases in this distinct gene expression and experimental validation is required to demonstrate their role as leukemogenic drivers.…”

“…This discrepancy is in part attributable to the different prevalence of genetic alterations across age. ALL may be of B-(B-ALL) or T-lymphoid (T-ALL) lineage, and comprises over thirty distinct subtypes characterized by germline and somatic genetic alterations that converge on distinct gene expression profiles [5][6][7][8][9][10][11][12]. These subtypes are defined by disease-initiating recurrent chromosomal gains and losses (hyperand hypodiploidy, and complex intrachromosomal amplification of chromosome 21); chromosomal rearrangements that deregulate oncogenes or encode chimeric fusion oncoproteins, importantly often including cryptic rearrangements not identifiable by conventional cytogenetic approaches, such as DUX4 and EPOR rearrangements; subtypes defined by single point mutations (e.g., PAX5 P80R or IKZF1 N159Y); subtypes defined by enhancer hijacking (e.g., BCL11B-rearrangements in T-ALL and lineage ambiguous leukemia) [5]; and subtypes that "phenocopy" established subtypes, with similar gene expression profile but different founding alterations (e.g., BCR-ABL1-like ALL and ETV6-RUNX1-like ALL) [7,[13][14][15].…”

Preventive Healthcare and Management for Acute Lymphoblastic Leukaemia in Adults: Case Report and Literature Review

“…Current well-established molecular subtypes with poor/intermediate prognoses are those involving BCR-ABL1 fusion, KMT2A fusions, TCF3-PBX1, and HLF fusions, and low hypodiploid. Double homeobox 4 gene (DUX4), myocyte enhancer factor 2D (MEF2D), and zinc finger protein 384 (ZNF384) are associated with DNA binding factor rearrangements [30]. Ph-like ALL constitutes several genetic alterations, including rearrangements of CRLF2, ABL-class genes, mutations or deletions activating the JAK-STAT or MAPK signaling pathways, other rare kinase alterations, JAK2, and EPOR [31].…”

“…IKZF1 is a significant transcription factor that affects the differentiation of B-cell precursors. The IKZF1 p.Asn159Tyr (N159Y) point mutation is rare in B-cell precursor acute lymphoblastic leukaemia [30]. Because molecular genetics is not available in our hospital, information on the genetic alterations of our patient was not identified.…”

Multi-omics molecular phenotyping of childhood acute lymphoblastic leukemia cell lines reveals novel drug vulnerabilities

“…Therefore, bridging the gap in therapeutic options for ALL will likely require development of both pharmacologic and cellular therapies; and this process will depend on deeper characterization of both the biomarkers and biology of non-responsive subtypes. While the genetic landscape of childhood ALL has been extensively studied by implementation of next generation genomic, transcriptomic, and epigenetic sequencing tools 10,11 , somatic mutations can only partially explain the underlying biology and phenotype, and approximately 25% of childhood ALL patients lack a detectable driving mutation 12 . Although genetic characterizations have improved risk stratification and hope of new molecular targets for therapy, the primary challenge of identifying novel and effective treatments for ALL is achieving more reliable clinical stratification that can improve therapeutic response 13 .…”