Leukemia, Acute Lymphoblastic
Description
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.
MappingIn a genomewide association study of 317 patients with ALL and 17,958 controls, Trevino et al. (2009) found an association between ALL and 2 SNPs on chromosome 10q21: rs10821936 (p = 1.4 x 10(-15), odds ratio (OR) of 1.91) and rs10994982 (p = 5.7 x 10(-9), OR of 1.62.) The SNPs were in linkage disequilibrium with each other and located in intron 3 of the ARID5B gene (608538). The patient cohort included 67 patients with T-cell leukemia. In addition, these SNPs also distinguished B-hyperdiploid ALL from other subtypes (rs10821936; p = 1.62 x 10(-5), OR of 2.17; rs10994982; p = 0.003, OR of 1.72). These specific findings were replicated in an independent validation cohort of 124 children with ALL (p = 0.003 and p = 0.0008, ORs of 2.45 and 2.86, respectively). The risk alleles were also associated with methotrexate accumulation and gene expression pattern in leukemic lymphoblasts. Trevino et al. (2009) concluded that germline variants can affect susceptibility to, and characteristics of, ALL and specific ALL subtypes.
In a genomewide association study of 2 case-control series, totaling 907 ALL cases and 2,398 controls, Papaemmanuil et al. (2009) also found an association between development of ALL and a SNP at 10q21.2 in the ARID5B gene (rs7089424, OR of 1.65, p = 6.69 x 10(-19)). The 10q21.2 risk association was selective for the B-hyperdiploid subtype. These data suggested that common low-penetrance susceptibility alleles may contribute to the risk of developing childhood ALL.
By genotyping 1,384 cases of precursor B-cell childhood ALL and 1,877 controls from Germany and the United Kingdom, Prasad et al. (2010) found a significant association between ALL and the ARID5B SNP rs7089424 (OR of 1.80; p = 5.90 x 10(-28)). This finding replicated the independent susceptibility locus for ALL at chromosome 10q21.2 previously reported by Trevino et al. (2009) and Papaemmanuil et al. (2009). The ALL2 locus on chromosome 7p12.2 and a locus on chromosome 14q11.2 (see below) were also replicated. Although there was no evidence of interactive effects between any of the 3 pairs of loci, the risk of ALL increased with an increasing number of risk alleles for the 3 loci. Prasad et al. (2010) concluded that these variants may underlie the risk of ALL in approximately 64% of cases.
Associations Pending Confirmation
In a genomewide association study of 2 case-control series, totaling 907 ALL cases and 2,398 controls, Papaemmanuil et al. (2009) found a suggestive association with a SNP at chromosome 14q11.2 in the CEBPE gene (600749) (rs2239633, OR of 1.34, p = 2.88 x 10(-7)).
By genotyping 1,384 cases of precursor B-cell childhood ALL and 1,877 controls from Germany and the United Kingdom, Prasad et al. (2010) found a significant association between ALL and CEBPE SNP rs2239633 (OR of 1.27; p = 4.90 x 10(-6)). This finding replicated the independent susceptibility locus for ALL at chromosome 14q11.2 previously reported by Papaemmanuil et al. (2009).
PathogenesisETV6-RUNX1 ALL
The ETV6/RUNX1 fusion gene (see 600618), found in 25% of childhood ALL cases, is acquired in utero but requires additional somatic mutations for overt leukemia. Papaemmanuil et al. (2014) used exome and low-coverage whole-genome sequencing to characterize secondary events associated with leukemic transformation. RAG (see 179615)-mediated deletions emerged as the dominant mutational process, characterized by recombination signal sequence motifs near breakpoints, incorporation of nontemplated sequence at junctions, approximately 30-fold enrichment at promoters and enhancers of genes actively transcribed in B-cell development, and an unexpectedly high ratio of recurrent to nonrecurrent structural variants. Single-cell tracking showed that this mechanism is active throughout leukemic evolution, with evidence of localized clustering and reiterated deletions. Integration of data on point mutations and rearrangements identified ATF7IP (613644) and MGA (616061) as tumor-suppressor genes in ALL. Papaemmanuil et al. (2014) concluded that a remarkably parsimonious mutational process transforms ETV6/RUNX1-positive lymphoblasts, targeting the promoters, enhancers, and first exons of genes that normally regulate B-cell differentiation.
PAX5 and IKZF1 Mutations
Lesions in the PAX5 (167414) and IKZF1 (602023) genes, encoding B-lymphoid transcription factors, occur in over 80% of cases of pre-B-cell ALL. By combining studies using chromatin immunoprecipitation with sequencing and RNA sequencing, Chan et al. (2017) identified a novel B-lymphoid program for transcriptional repression of glucose and energy supply. The metabolic analyses revealed that PAX5 and IKZF1 enforce a state of chronic energy deprivation, resulting in constitutive activation of the energy-stress sensor AMPK (see 602739). Dominant-negative mutants of PAX5 and IKZF1 however, relieved this glucose and energy restriction. In a transgenic pre-B ALL mouse model, the heterozygous deletion of Pax5 increased glucose uptake and ATP levels by more than 25-fold. Reconstitution of PAX5 and IKZF1 in samples from patients with pre-B ALL restored a nonpermissive state and induced energy crisis and cell death. A CRISPR/Cas9-based screen of PAX5 and IKZF1 transcriptional targets identified the products of NR3C1 (138040), encoding the glucocorticoid receptor, TXNIP (605051), encoding a glucose feedback sensor, and CNR2 (605051), encoding a cannabinoid receptor, as central effectors of B-lymphoid restriction of glucose and energy supply. Notably, transport-independent lipophilic methyl-conjugates of pyruvate and tricarboxylic acid cycle metabolites bypassed the gatekeeper function of PAX5 and IKZF1 and readily enabled leukemic transformation. Conversely, pharmacologic TXNIP and CNR2 agonists and a small-molecule AMPK inhibitor strongly synergized with glucocorticoids, identifying TXNIP, CNR2, and AMPK as potential therapeutic targets. Furthermore, these results provided a mechanistic explanation for the empirical finding that glucocorticoids are effective in the treatment of B-lymphoid but not myeloid malignancies. Thus, B-lymphoid transcription factors function as metabolic gatekeepers by limiting the amount of cellular ATP to levels that are insufficient for malignant transformation.
Central Nervous System Metastasis
In mice, Yao et al. (2018) showed that ALL cells in the circulation are unable to breach the blood-brain barrier; instead, they migrate into the central nervous system (CNS) along vessels that pass directly between vertebral or calvarial bone marrow and the subarachnoid space. The basement membrane of these bridging vessels is enriched in laminin (see 150320), which is known to coordinate pathfinding of neuronal progenitor cells in the CNS. The laminin receptor alpha-6 integrin (ITGA6; 147556) is expressed in most cases of ALL. Yao et al. (2018) found that alpha-6 integrin-laminin interactions mediated the migration of ALL cells towards the cerebrospinal fluid in vitro. Mice with ALL xenografts were treated with either a PI3K-delta (PIK3CD; 602839) inhibitor, which decreased alpha-6 integrin expression on ALL cells, or specific alpha-6 integrin-neutralizing antibodies, and showed significant reductions in ALL transit along bridging vessels, blast counts in the cerebrospinal fluid, and CNS disease symptoms despite minimally decreased bone marrow disease burden. Yao et al. (2018) concluded that alpha-6 integrin expression, which is common in ALL, allows cells to use neural migratory pathways to invade the CNS.
Molecular GeneticsSomatic 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; 136351.0007; 136351.0009). 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.
Ntziachristos et al. (2014) delineated the role of the H3K27 demethylases JMJD3 (KDM6B; 611577) and UTX (KDM6A; 300128) in T-ALL. The authors showed that JMJD3 is essential for the initiation and maintenance of T-ALL, as it controls important oncogenic gene targets by modulating H3K27 methylation. By contrast, they found that UTX functions as a tumor suppressor and is frequently genetically inactivated in T-ALL. Moreover, Ntziachristos et al. (2014) demonstrated that the small molecule inhibitor GSKJ4 affects T-ALL growth by targeting JMJD3 activity. Ntziachristos et al. (2014) concluded that 2 proteins with a similar enzymatic function can have opposing roles in the context of the same disease, paving the way for treating hematopoietic malignancies with a novel category of epigenetic inhibitors.
For discussion of an association between ALL and somatic mutation in the GNB1 gene, see 139380.
Heterozygous activating mutations in NT5C2 (600417) are present in about 20% of relapsed pediatric T-cell ALL and in 3 to 10% of relapsed B-precursor ALL, and an arg367-to-gln (R367Q) change is the most common NT5C2 mutation found in relapsed ALL. Tzoneva et al. (2018) used a conditional and inducible leukemia model to demonstrate that expression of NT5C2(R367Q) induces resistance to chemotherapy with 6-mercaptopurine at the cost of impaired leukemia cell growth and leukemia-initiating cell activity. The loss-of-fitness phenotype of NT5C2 +/R367Q mutant cells was associated with excess export of purines to the extracellular space and depletion of the intracellular purine-nucleotide pool. Consequently, blocking guanosine synthesis by inhibition of inosine-5-prime-monophosphate dehydrogenase (IMPDH) induced increased cytotoxicity against NT5C2-mutant leukemia lymphoblasts. Tzoneva et al. (2018) concluded that these results identified the fitness cost of NT5C2 mutation and resistance to chemotherapy as key evolutionary drivers that shape clonal evolution in relapsed ALL and supported a role for IMPDH inhibition in the treatment of ALL.
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.
Clinical ManagementResistance to tyrosine kinase inhibitors (TKIs) develops in virtually all cases of Philadelphia chromosome-positive acute lymphoblastic leukemia. Duy et al. (2011) reported the discovery of a novel mechanism of drug resistance that is based on protective feedback signaling of leukemia cells in response to treatment with TKIs. In Philadelphia chromosome-positive acute lymphoblastic leukemia cells, Duy et al. (2011) identified BCL6 (109565) as a central component of this drug-resistance pathway and demonstrated that targeted inhibition of BCL6 leads to eradication of drug-resistant and leukemia-initiating subclones.
Mutations that deregulate NOTCH1 (190198) and RAS/PI3K (see 601232)/AKT signaling are prevalent in T-ALL and often coexist. Dail et al. (2014) showed that the PI3K inhibitor GDC-0941 is active against primary T-ALLs from wildtype and Kras(G12D) mice; addition of the MEK (see 176872) inhibitor PD0325901 increases its efficacy. Mice invariably relapsed after treatment with drug-resistant clones, most of which unexpectedly showed reduced levels of activated NOTCH1 protein, downregulated many NOTCH1 target genes, and exhibited cross-resistance to gamma-secretase inhibitors. Multiple resistant primary T-ALLs that emerged in vivo did not contain somatic NOTCH1 mutations present in the parental leukemia, and resistant clones upregulated PI3K signaling. Consistent with these data, inhibition of NOTCH1 activated the PI3K pathway, providing a likely mechanism for selection against oncogenic NOTCH1 signaling. Dail et al. (2014) concluded that these studies validated PI3K as a therapeutic target in T-ALL and raised the unexpected possibility that dual inhibition of PI3K and NOTCH1 signaling could promote drug resistance in T-ALL.
Methotrexate is used as the standard of care in the treatment of the most common pediatric malignancy, acute lymphoblastic leukemia (ALL), with relatively high success rates that unfortunately are accompanied by severe toxicity. Kanarek et al. (2018) found that young patients with ALL that showed high expression of HAL (609457) in the ALL cells have significantly higher survival rates compared to patients in the same study with low HAL expression. Expression levels of expression levels of SLC19A1 (600424), which encodes the transporter for methotrexate, as well as the genes AMDHD1 and FTCD (606806), encoding histidine degradation pathway enzymes, showed no significant association with patient survival. Kanarek et al. (2018) concluded that endogenous expression levels of HAL, which encodes the rate-limiting enzyme of the histidine degradation pathway, are associated with the sensitivity of cancer cell lines to methotrexate, and the overall survival of patients with ALL who are treated with methotrexate. These findings suggested that HAL expression might serve as a clinical predictor for better responders to methotrexate treatment among patients with ALL and may be informative for decisions regarding therapy strategies. Furthermore, both genetic perturbation and dietary enhancement of the pathway changed the sensitivity of hematopoietic cancer cells to the chemotherapy. As standard protocols for administering methotrexate are often accompanied by severe toxicity, Kanarek et al. (2018) suggested that dietary supplementation with histidine could represent a relatively low-risk intervention that might enable reduced dosing of this toxic agent and therefore a greater clinical benefit.