LEUKEMIA, ACUTE LYMPHOCYTIC, SUSCEPTIBILITY TO, 1, INCLUDED
LEUKEMIA, B-CELL ACUTE LYMPHOBLASTIC, SUSCEPTIBILITY TO, INCLUDED
LEUKEMIA, T-CELL ACUTE LYMPHOBLASTIC, SUSCEPTIBILITY TO, INCLUDED
ALL LEUKEMIA, ACUTE LYMPHOBLASTIC, SUSCEPTIBILITY TO, 1, INCLUDED
LEUKEMIA, ACUTE LYMPHOBLASTIC, B-HYPERDIPLOID, SUSCEPTIBILITY TO, INCLUDED
ALL1, INCLUDED
Acute lymphoblastic leukemia (ALL), also known as acute lymphocytic leukemia, is a subtype of acute leukemia, a cancer of the white blood cells. Somatically acquired mutations in several genes have been identified in ALL lymphoblasts, cells in the ... Acute lymphoblastic leukemia (ALL), also known as acute lymphocytic leukemia, is a subtype of acute leukemia, a cancer of the white blood cells. Somatically acquired mutations in several genes have been identified in ALL lymphoblasts, cells in the early stages of differentiation. Germline variation in certain genes may also predispose to susceptibility to ALL (Trevino et al., 2009). - Genetic Heterogeneity of Acute Lymphoblastic Leukemia A susceptibility locus for acute lymphoblastic leukemia (ALL1) has been mapped to chromosome 10q21. See also ALL2 (613067), which has been mapped to chromosome 7p12.2; and ALL3 (615545), which is caused by mutation in the PAX5 gene (167414) on chromosome 9p.
A t(9;22) translocation occurs in greater than 90% of chronic myelogeneous leukemia (CML; 608232), 25 to 30% of adult and 2 to 10% of childhood acute lymphoblastic leukemia, and rare cases of acute ... - Somatic Mutations A t(9;22) translocation occurs in greater than 90% of chronic myelogeneous leukemia (CML; 608232), 25 to 30% of adult and 2 to 10% of childhood acute lymphoblastic leukemia, and rare cases of acute myelogenous leukemia. The translocation, known as the Philadelphia chromosome, results in the head-to-tail fusion of the BCR (151410) and ABL1 (189980) genes (see review of Chissoe et al., 1995). Clark et al. (1987) demonstrated that Philadelphia chromosome-positive ALL cells express unique Abl-derived tyrosine kinases of 185 and 180 kD that are distinct from the Bcr, Abl-derived 210-kD protein of CML. In ALL, Fainstein et al. (1987) found that ABL is translocated into the 5-prime region of the BCR gene. The consequence of this is the expression of a fused transcript in which the first exon of BCR is linked to the second ABL exon. This transcript encodes a 190-kD protein kinase. Kurzrock et al. (1987) found a novel Abl protein product in Philadelphia chromosome-positive acute lymphoblastic leukemia. They suggested that alternative mechanisms of activation of Abl exist and that a different mechanism may apply in human acute lymphoid leukemia as opposed to myeloid malignancies. In T-cell acute lymphoblastic leukemia (T-ALL), transcription factors are known to be deregulated by chromosomal translocations. Graux et al. (2004) described the extrachromosomal (episomal) amplification of ABL1 in 5 of 90 (5.6%) individuals with T-ALL. Molecular analyses delineated the amplicon as a 500-kb region from band 9q34, containing the oncogenes ABL1 and NUP214 (114350). They detected the ABL1/NUP214 fusion transcript in cell lines derived from 5 individuals with the ABL1 amplification, in cell lines from 5 of 85 (5.8%) additional individuals with T-ALL, and in 3 of 22 T-ALL cell lines. The constitutively phosphorylated tyrosine kinase ABL1/NUP214 was found to be sensitive to the tyrosine kinase inhibitor imatinib. The recurrent cryptic ABL1/NUP214 rearrangement was associated with increased expression of HOX11 (186770) and HOX11L2 (604640) and deletion of CDKN2A (600160), consistent with a multistep pathogenesis of T-ALL. Somatic mutations in the FLT3 (136351) and BAX (600040) genes have been identified in cell lines from patients with acute lymphocytic leukemia. Meijerink et al. (1998) found that approximately 21% of human hematopoietic malignancy cell lines had somatic mutations in the BAX gene, perhaps most commonly in acute lymphoblastic leukemia. Both T-cell and B-cell lines contained BAX somatic mutations. Approximately half were nucleotide insertions or deletions within a deoxyguanosine (G8) tract (see 600040.0004), resulting in a proximal frameshift and loss of immunodetectable BAX protein. Armstrong et al. (2004) found that 6 (25%) of 25 hyperdiploid ALL samples had somatic mutations in the FLT3 gene (see 136351.0003; 136531.0007; 136531.0009). Three mutations were novel in-frame deletions within a 7-amino acid region of the receptor juxtamembrane domain. In 3 samples from patients whose disease would relapse, FLT3 mutations were identified. These data suggested that patients with hyperdiploid or relapsed ALL in childhood might be considered candidates for therapy with small-molecule inhibitors of FLT3. In a genomewide analysis of leukemic cells from 242 pediatric ALL patients using high resolution SNP arrays and genomic DNA sequencing, Mullighan et al. (2007) identified mutations in genes encoding principal regulators of B-lymphocyte development and differentiation in 40% of B-progenitor ALL cases. Deletions were detected in IKZF1 (603023), IKZF3 (606221),TCF3 (147141), EBF1 (164343), and LEF1 (153245). The PAX5 (167414) gene was the most frequent target of somatic mutation, being altered in 31.7% of cases. Mullighan et al. (2009) reported a recurring interstitial deletion of pseudoautosomal region 1 of chromosomes X and Y in B-progenitor ALL that juxtaposes the first, noncoding exon of P2RY8 (300525) with the coding region of CRLF2 (300357). They identified the P2RY8/CRLF2 fusion in 7% of individuals with B-progenitor ALL and 53% of individuals with ALL associated with Down syndrome. CRLF2 alteration was associated with activating JAK mutations, and expression of human P2RY8/CRLF2 together with mutated mouse Jak2 (147796) resulted in constitutive JAK-STAT activation and cytokine-independent growth of Ba/F3 cells overexpressing IL7 receptor-alpha (IL7R; 146661). Mullighan et al. (2009) concluded that rearrangement of CRLF2 and JAK mutations together contribute to leukemogenesis in B-progenitor ALL. Van Vlierberghe et al. (2010) identified somatic inactivating mutations and deletions of the PHF6 gene in 16% of pediatric and 38% of adult primary T-ALL samples, most of which were derived from male patients. The authors noted that T-ALL shows an increased incidence in males. Loss of PHF6 was associated with leukemias driven by aberrant expression of the homeobox transcription factor oncogenes TLX1 (186770) and TLX3 (604640). The findings suggested that PHF6 is an X-linked tumor suppressor in T-ALL. Anderson et al. (2011) examined the genetic architecture of cancer at the subclonal and single-cell level and in cells responsible for cancer clone maintenance and propagation in childhood acute lymphoblastic leukemia in which the ETV6 (600618)/RUNX1 (151385) gene fusion is an early or initiating genetic lesion followed by a modest number of recurrent or driver copy number alterations. By multiplexing fluorescence in situ hybridization probes for these mutations, up to 8 genetic abnormalities could be detected in single cells, a genetic signature of subclones identified, and a composite picture of subclonal architecture and putative ancestral trees assembled. Anderson et al. (2011) observed that subclones in acute lymphoblastic leukemia have variegated genetics and complex nonlinear or branching evolutionary histories. Copy number alterations are independently and reiteratively acquired in subclones of individual patients, and in no preferential order. Clonal architecture is dynamic and is subject to change in the lead-up to a diagnosis and in relapse. Leukemia-propagating cells, assayed by serial transplantation in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) IL2R-gamma (308380)-null mice, are also genetically variegated, mirroring subclonal patterns, and vary in competitive regenerative capacity in vivo. Mullighan et al. (2011) resequenced 300 genes in matched diagnosis and relapse samples from 23 patients with ALL. This identified 52 somatic nonsynonymous mutations in 32 genes, many of which were novel, including the transcriptional coactivators CREBBP (600140) and NCOR1 (600849), the transcription factors ERG (165080), SPI1 (165170), TCF4 (602272), and TCF7L2 (602228), components of the Ras signaling pathway (see 190070), histone genes (e.g., 602810), genes involved in histone modification (CREBBP and CTCF, 604167), and genes previously shown to be targets of recurring DNA copy number alteration in ALL. Analysis of an extended cohort of 71 diagnosis-relapse cases and 270 acute leukemia cases that did not relapse found that 18.3% of relapse cases had sequence or deletion mutations of CREBBP, which encodes the transcriptional coactivator and histone acetyltransferase CREB-binding protein. The mutations were either present at diagnosis or acquired at relapse, and resulted in truncated alleles or deleterious substitutions in conserved residues of the histone acetyltransferase domain. Functionally, the mutations impaired histone acetylation and transcriptional regulation of CREBBP targets. Several mutations acquired at relapse were detected in subclones at diagnosis, suggesting that the mutations may confer resistance to therapy. Zenatti et al. (2011) identified heterozygous somatic mutations in the IL7R (146661) gene on chromosome 5p13 in 17 (9%) of 201 T-cell acute lymphoblastic leukemia samples from 3 independent cohorts. All mutations affected exon 6, in the juxtamembrane-transmembrane domain at the interface with the extracellular region, and were shown in several cell lines to result in ligand-independent constitutive activation of IL7R-mediated downstream signaling pathways, most prominently PI3K-Akt (see 164730), JAK1 (147795), and STAT5 (601511). JAK3 (600173) signaling was not involved. Most IL7R mutations (14/17; 82%) created an unpaired cysteine residue in the interface, leading to homotypic dimerization and/or oligomerization and thus bypassing the requirement for ligand-dependent activation. These mutations were enriched in the T-ALL subgroup comprising TLX3 (604640)-rearranged and HOXA (614060)-deregulated cases. In vitro and in vivo mouse studies demonstrated the oncogenic potential of the IL7R mutants. T-ALL cells carrying the IL7R mutations were sensitive to inhibition of the JAK-STAT pathway, suggesting therapeutic implications. Ntziachristos et al. (2012) reported the presence of loss-of-function mutations and deletions of the EZH2 (601573) and SUZ12 (606245) genes, which encode crucial components of the polycomb repressive complex-2 (PRC2), in 25% of T-ALLs. To further study the role of PRC2 in T-ALL, Ntziachristos et al. (2012) used NOTCH1 (190198)-dependent mouse models of the disease, as well as human T-ALL samples, and combined locus-specific and global analysis of NOTCH1-driven epigenetic changes. These studies demonstrated that activation of NOTCH1 specifically induces loss of the repressive mark lys27 trimethylation of histone-3 (H3K27me3) by antagonizing the activity of PRC2. Ntziachristos et al. (2012) concluded that their studies suggested a tumor suppressor role for PRC2 in human leukemia and suggested a hitherto unrecognized dynamic interplay between oncogenic NOTCH1 and PRC2 function for the regulation of gene expression and cell transformation. Using exome sequencing in 67 T-cell ALLs, De Keersmaecker et al. (2013) detected protein-altering mutations in 508 genes. Consideration of genes that were mutated in at least 2 samples and were significantly more mutated than the local background mutation rate identified 15 candidate oncogenic driver genes, 7 of which were novel. Adult (15 years of age or older) samples showed 2.5 times more somatic protein-altering mutations than those from children (21.1 vs 8.2), and 2.7 times more mutations in candidate driver genes than those from children. De Keersmaecker et al. (2013) identified CNOT3 (604910) as a tumor suppressor mutated in 7 of 89 (7.9%) adult T-ALLs; its knockdown caused tumors in a sensitized Drosophila eye cancer model in which the Notch ligand Delta (see 606582) is overexpressed in the developing eyes. In addition, De Keersmaecker et al. (2013) identified mutations affecting the ribosomal proteins RPL5 (603634) and RPL10 (312173) in 12 of 122 (9.8%) pediatric T-ALLs, with recurrent alterations in RPL10 of arg98, an invariant residue from yeast to human. Yeast and lymphoid cells expressing the RPL10 arg98 to ser mutant showed a ribosome biogenesis defect. Jaffe et al. (2013) profiled global histone modifications in 115 cancer cell lines from the Cancer Cell Line Encyclopedia. One signature was characterized by increased H3K36me2, exhibited by several lines harboring translocations in the NSD2 methyltransferase (WHSC1; 602952). An NSD2 glu1099-to-lys (E1099K) variant was identified in nontranslocated ALL cell lines sharing this signature. Ectopic expression of the variant induced a chromatin signature characteristic of NSD2 hyperactivation and promoted transformation. NSD2 knockdown selectively inhibited the proliferation of NSD2-mutant lines and impaired the in vivo growth of an NSD2-mutant ALL xenograft. Sequencing analysis of greater than 1,000 pediatric cancer genomes identified the NSD2 E1099K alteration in 14% of t(12;21) ETV6-RUNX1-containing ALLs. - Somatic Mutations in Early T-Cell Precursor ALL Zhang et al. (2012) performed whole-genome sequencing of 12 early T-cell precursor (ETP) ALL cases and assessed the frequency of the identified somatic mutations in 94 T-cell ALL cases. ETP ALL was characterized by activating mutations in genes regulating cytokine receptor and RAS signaling (67% of cases; NRAS, 164790; KRAS, 190070; FLT3, 136351; IL7R, JAK3, JAK1, SH2B3, 605093; and BRAF, 164757), inactivating lesions disrupting hematopoietic development (58%; GATA3, 131320; ETV6, 600618; RUNX1, 151385; IKZF1, 603023; and EP300, 602700), and histone-modifying genes (48%; EZH2, 601573; EED, 605984; SUZ12, 606245; SETD2, 612778; and EP300). Zhang et al. (2012) also identified new targets of recurrent mutation including DNM2 (602378), ECT2L, and RELN (600514). The mutational spectrum is similar to myeloid tumors, and moreover, the global transcriptional profile of ETP ALL was similar to that of normal and myeloid leukemia hematopoietic stem cells. Zhang et al. (2012) concluded that addition of myeloid-directed therapies might improve the poor outcome of ETP ALL.