Advances in the Genetics of High-Risk Childhood B-Progenitor Acute Lymphoblastic Leukemia and Juvenile Myelomonocytic Leukemia: Implications for Therapy

Abstract

Hematologic malignancies of childhood comprise the most common childhood cancers. These neoplasms derive from the pathologic clonal expansion of an abnormal cancer-initiating cell and span a diverse spectrum of phenotypes, including acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), myeloproliferative neoplasms (MPN), and myelodysplastic syndromes (MDS). Expansion of immature lymphoid or myeloid blasts with suppression of normal hematopoiesis is the hallmark of ALL and AML, whereas MPN is associated with proliferation of 1 or more lineages that retain the ability to differentiate, and MDS is characterized by abnormal hematopoiesis and cytopenias. The outcomes for children with the most common childhood cancer, B-progenitor ALL (B-ALL), in general, is quite favorable, in contrast to children affected by myeloid malignancies. The advent of highly sensitive genomic technologies reveals the remarkable genetic complexity of multiple subsets of high-risk B-progenitor ALL, in contrast to a somewhat simpler model of myeloid neoplasms, although a number of recently discovered alterations displayed by both types of malignancies may lead to common therapeutic approaches. This review outlines recent advances in our understanding of the genetic underpinnings of high-risk B-ALL and juvenile myelomonocytic leukemia, an overlap MPN/MDS found exclusively in children, and we also discuss novel therapeutic approaches that are currently being tested in clinical trials. Recent insights into the clonal heterogeneity of leukemic samples and the implications for diagnostic and therapeutic approaches are also discussed. Clin Cancer Res; 18(10); 2754-67. Ó2012 AACR. Acute Lymphoblastic LeukemiaAcute lymphoblastic leukemia (ALL) is the commonest childhood malignancy and, despite progressive improvements in the outcome of therapy, remains the leading cause of cancer-related death in children and young adults (1). ALL is characterized by accumulation of immature lymphoid progenitors in the bone marrow, peripheral blood, and central nervous system and results in death from the consequences of bone marrow failure: anemia, neutropenia and infection, and thrombocytopenia and bleeding. Although these features are common to all patients, ALL represents a remarkably diverse range of subtypes characterized by distinct constellations of gross and submicroscopic genetic alterations, including chromosomal translocations, structural variants, and DNA sequence mutations.Many of these lesions are central events in leukemogenesis, and several are also important determinants of the risk of treatment failure and relapse. General overviews of the genetic basis of ALL may be found in several recent excellent reviews (2-6). This review is part of a series of articles in this issue reviewing new genetic insights and therapeutic opportunities in childhood malignancies (7-11). Here, we briefly review key chromosomal rearrangements in ALL and then focus on several high-risk subtypes, which have hitherto been poorly understood and for which r...

Mutations in TP53 and JAK2 are independent prognostic biomarkers in B-cell precursor acute lymphoblastic leukaemia

“…These mutations involved genes associated with RAS signalling (48% e.g., NRAS, KRAS, PTPN11, FLT3, BRAF and NF1 ), B-cell differentiation and development (18% e.g., PAX5, IKZF1, EBF1, VPREB1 ), JAK/STAT signalling (11% e.g., JAK1, JAK2, IL7R and CRLF2 ), cell cycle regulation and tumour suppression (6% e.g., TP53, RB1, CDKN2A/B, PTEN and BTG1 ), and non-canonical pathways (9%, e.g., ETV6, CREBBB and TBL1XR1 ) (Harrison, 2011; Mullighan, 2011; Pui et al , 2011; Roberts and Mullighan, 2011; Iacobucci et al , 2012; Loh and Mullighan, 2012; Gowda and Dovat, 2013; Inaba et al , 2013; Chiaretti et al , 2014a; Chiaretti et al , 2014b; Woo et al , 2014). However, the prognostic impact of these mutations as predictors of clinical course, outcome and response to therapy is still being explored.…”

VPREB1 deletions occur independent of lambda light chain rearrangement in childhood acute lymphoblastic leukemia

“…With the introduction of single-nucleotide polymorphism (SNP) microarray technology, there has been a recent explosion in genomic investigations and discovery of recurrent alterations in B-ALL, such as PAX5, IKZF1, JAK2 and CRLF2 . 1 Deletions of the VPREB1 gene, a component of the surrogate light chain of the pre-B-cell receptor (pre-BCR), have been observed in childhood B-ALL, 2, 3, 4, 5, 6, 7 and have been suggested to result from recombination activating gene (RAG) activation and variable (joining) diversity (V(D)J) recombination based on VPREB1 ’s location in the immunoglobulin lambda locus ( IGL@ ). 3, 6, 7 In a recent study of relapsed patients with ETV6-RUNX1 translocations, focal VPREB1 deletions were presumed to be involved in leukemogenesis but were not the focus of the reported findings.…”

The Future Is Now: Chimeric Antigen Receptors as New Targeted Therapies for Childhood Cancer

“…Dramatic progress in our understanding of genomics (83, 84), cancer biology (85), and immunology (39) is fueling exciting new progress in the search for more effective and less toxic targeted therapies for childhood cancer (86). Among the most novel and promising of these approaches are CAR-based cell therapies that combine advances in genetic engineering and adoptive immunotherapy.…”