Ongoing whole-genome sequencing projects in various malignancies are yielding terabytes of data and abundant new biological insights. The latest hematologic neoplasm targeted for investigation is a recently characterized subtype of acute lymphocytic leukemia (ALL), “early T-cell precursor (ETP)” ALL.
About 15 percent of ALL cases are of T-cell lineage, defined by cytoplasmic expression of CD3, a component of the T-cell receptor. CD3-positive leukemic blasts frequently co-express other T-lineage-associated markers, such as CD1a, CD2, CD4, CD5, CD7, or CD8. There are three immunologic subtypes of T-lineage ALL corresponding to different stages of T-cell ontogeny: thymic (also referred to as cortical) T-ALL, which expresses CD1a, with or without surface CD3 expression, and also expresses CD2 and CD4 or CD8; mature (medullary) T-ALL, which expresses surface CD3 but not CD1a; and ETP ALL, which expresses neither surface CD3 nor CD1a.
ETP ALL is also characterized by weak or absent expression of CD5, lack of expression of CD4 and CD8, frequent aberrant expression of myeloid lineage markers including CD33, and a uniform gene expression profile similar to that of murine early T-cell precursors.1 The probable cell of origin of ETP ALL is also called the “double negative 1” (DN1) thymocyte, which is capable of both T-cell and myeloid differentiation, but cannot follow a B-cell differentiation program.2 ETP ALL represents about 15 percent of T-ALL and is associated with a poorer prognosis and higher risk of treatment failure in both children and adults compared with thymic (cortical) T-ALL. Several leukemia groups are testing a strategy of referring these high-risk patients for stem cell transplantation.3 Until now, molecular genetic insights into this uncommon subset have been limited.
A multi-institutional consortium, led by investigators at St. Jude Children’s Research Hospital in Memphis and the Genome Institute at Washington University in St. Louis, performed whole-genome sequencing of 12 ETP ALL samples, then assessed the frequency of identified somatic mutations in 94 additional T-cell ALL cases, including 52 ETP ALL cases and 42 other types of pediatric T-ALL. The investigators observed that the average non-silent coding mutation rate was nine per case, similar to previous reports of acute myeloid leukemia (AML, ~8 mutations/case), but a mutation rate three- to four-fold less than for common adult tumors such as prostate, breast, or lung carcinoma (23-302 mutations/case).
Specific recurrent changes in ETP ALL included activating mutations in genes regulating cytokine receptor and RAS signaling (e.g., NRAS, KRAS, FLT3, IL7R, JAK3, JAK1,SH2B3, and BRAF), which were much more frequent in ETP ALL (67% of cases) than other T-ALL (19%). In the case of IL7R, clonogenic assays of murine cells expressing mutant alleles demonstrated enhanced growth factor-independent replating potential compared with control cells, confirming that such mutations give cells a clonal advantage. Furthermore, inactivating lesions predicted to impair hematopoietic development and differentiation(e.g., GATA3, ETV6, RUNX1, IKZF1, and EP300) were common in ETP ALL (58% of cases), as were mutations in histone-modifying genes (e.g., EZH2, EED, SUZ12,SETD2, and EP300; 48%), particularly members of the polycomb repressive complex PRC2.
Notably, this mutational spectrum is more similar to myeloid neoplasms than it is to other ALL subtypes. Coupled with the unique immunophenotypic profile of ETP ALL, the findings raise the possibility that the addition of myeloid-directed therapies – such as high-dose cytarabine or, in cases that express CD33, gemtuzumab ozogamicin – might improve the poor outcomes currently associated with ETP ALL.
Among the newly identified recurrent mutations in ETP ALL that need to be explored further are DNM2, encoding dynamin 2, a GTPase family member with diverse cellular functions; ECT2L, encoding “epithelial cell transforming sequence 2 oncogene gene like,” a putative guanine nucleotide exchange factor of uncertain function; and RELN, encoding reelin, a secreted extracellular matrix protein critical for normal neuronal migration (congenital mutations in RELN cause the tragic brain formation defect lissencephaly). For several genes, both deleterious germline and somatic mutations were detected in the same gene, similar to other pediatric cancers.
In Brief
ETP ALL is important to recognize as a unique subtype of ALL, as it may require different treatment from other ALL types. While the discovery of a unique ETP ALL-associated mutation profile with a high frequency of mutations activating cytokine and RAS signaling, impairing differentiation, and altering histone function overlaps with AML, it remains to be seen whether incorporation of cytotoxic agents currently recognized as useful in AML can alter outcomes in ETP ALL, or whether more substantive improvements will need to await the advent of more narrowly targeted treatments.
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Competing Interests
Drs. Steensma and DeAngelo indicated no relevant conflicts of interest.
