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Acute Lymphoblastic Leukemia (ALL)

Acute lymphoblastic leukemia (ALL) is the most common childhood tumor, and although more than 80% of children are cured, relapsed ALL remains a leading cause of childhood morbidity and mortality. ALL, like cancer in general, probably arises from interactions between exogenous or endogenous exposures, genetic susceptibility, and chance. These factors account for the roughly 1 in 2000 risk of the disease in childhood (0–15 years). With increasing age, the frequency of genetic alterations associated with favorable outcome declines and alterations associated with poor outcome such as BCR-ABL1 are more common. Except for tyrosine kinase inhibitors (TKIs) such as imatinib in the treatment of BCR-ABL1+ leukemia, current therapies do not target specific genetic alterations and are associated with substantial short- and long-term toxicities that limit further dose escalation. Therefore, there is great interest in the use of high-resolution genomic profiling to characterize the genetic basis of leukemogenesis, to understand and predict treatment failure, and to provide novel markers that may be integrated into diagnostic testing and be targeted with novel therapies.

High-resolution profiling of genetic alterations has transformed understanding of the genetic basis of ALL. That most childhood cases harbor gross chromosomal alterations has been known for several decades. In B-cell disease, these alterations include high hyperdiploidy with non-random gain of at least five chromosomes (including X, 4, 6, 10, 14, 17, 18, and 21); hypodiploidy with fewer than 44 chromosomes; and recurring translocations including t(12;21)(p13;q22) encoding ETV6–RUNX1, t(1;19)(q23;p13) encoding TCF3-PBX1, t(9;22)(q34;q11) encoding BCR–ABL1, rearrangement of MLL at 11q23 with a wide range of partner genes, and rearrangement of MYC into antigen receptor gene loci. Dysregulation of TAL1, TLX1, TLX3, and LYL1, particularly by rearrangement into T-cell antigen receptor loci, often occurs in T lymphoblastic leukemia. These changes are of key importance in both pathogenesis and clinical management. Many chromosomal rearrangements disrupt genes that regulate normal haemopoiesis and lymphoid development (e.g., ETV6, RUNX1), activate oncogenes (e.g., MYC), or constitutively activate tyrosine kinases (e.g., ABL1). Several are significantly associated with outcomes, particularly in B-cell disease, and are used in risk stratification. High hyperdiploidy and ETV6–RUNX1 rearrangement are associated with favorable outcome, whereas low hypodiploidy and MLL rearrangement (especially in infants and adults) are associated with poor prognosis in both children and adults.

Next-generation sequencing enables comprehensive identification of the genetic changes in leukemia. Simultaneous sequencing of hundreds of thousands of nucleic acids (so-called massively parallel sequencing) might be used to identify sequence mutations and structural variants in the encoding portion of the genome (exome sequencing), the transcriptome (mRNA sequencing), or the entire genome. In 187 cases of high-risk B lymphoblastic leukemia, 120 candidate genes and pathways targeted by DNA copy number alterations were sequenced; a high frequency of alterations targeting B lymphoid development (68%), the TP53–RB1 tumor suppressor pathway (54%), Ras signaling (50%), and Janus kinases (11%), and recurring mutations in genes including CREBBP, ETV6, TBL1XR1, ASMTL, MUC4, and ADARB2 were identified. Whole genome sequencing of 12 cases and mutational-recurrence testing in an additional 94 patients with T lymphoblastic leukemia (52 of whom had the early T-cell precursor form) showed that three pathways frequently mutated in acute myeloid leukemia were mutated at high frequency in early T-cell precursor disease—specifically, inactivating mutations targeting hemopoietin and lymphoid development (including ETV6, GATA3, RUNX1, and IKZF1), mutations driving aberrant cytokine receptor and Ras signaling (NRAS, FLT3, KRAS, JAK1, JAK3, and IL7R), and deleterious mutations in chromatin-modifying genes, most notably components of polycomb repressor complex 2 (EED, EZH2, and SUZ12).

Accurate, comprehensive identification of the full range of genetic alterations in ALL is important for diagnosis, risk stratification, implementation of targeted therapy, and sensitive monitoring of treatment response. Creative Biogene, as a leading biotechnology company, can offer various ALL pathway-related products including stable cell lines, viral particles and clones for your pathogenesis study and drug discovery projects.

  1. Iacobucci I , Mullighan C G . Genetic Basis of Acute Lymphoblastic Leukemia. Journal of Clinical Oncology, 2017, 35(9):975-983.
  2. Mullighan C G . The molecular genetic makeup of acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program, 2012, 2012(1):389-396.
  3. Inaba H, Greaves M, Mullighan C G. Acute lymphoblastic leukaemia. The Lancet, 2013, 381(9881): 1943-1955.
  4. Chiaretti S , Zini G , Bassan R . DIAGNOSIS AND SUBCLASSIFICATION OF ACUTE LYMPHOBLASTIC LEUKEMIA. Mediterranean Journal of Hematology and Infectious Diseases, 2014, 6(1).

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