Genetic Basis of an Aggressive Pediatric Leukemia

Contents: Early T-cell ALLWhole-genome SequencingGenetic Architecture of ETP-ALLA Stem-cell Leukemia

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, comprising two forms: B-cell ALL (85% of cases) and T-cell ALL (15% of cases). In this week’s issue of Nature, Jinghui Zhang and colleagues report the whole-genome sequencing of 12 cases of early T-cell precursor acute lymphoblastic leukemia (ETP-ALL), a recently described and aggressive subtype of T-ALL whose genetic basis was unknown. This is the first major publication of the Pediatric Cancer Genome Project, a collaborative effort between St. Jude Children’s Research Hospital and Washington University in St. Louis.

Early T-cell precursor acute lymphoblastic leukemia

ETP-ALL is associated with a high risk of treatment failure, and bears some distinct characteristics:

  1. Lack of expression of T-lineage cell surface markers CD1a and CD8
  2. Weak or absent expression of CD5
  3. Aberrant expression of myeloid and hematopoietic stem cell markers (such asCD13, CD33, CD34, CD117)
  4. “Early” cells that can differentiate into T-cell and myeloid lineages (but not B-cell).
  5. Gene expression profiles remniscent of the mouse early T-cell precursor

ETP-ALL tumors exhibit an unusually high burden of DNA copy number alterations, but no unifying genetic have been identified.

Whole-Genome Sequencing of ETP-ALL

Zhang et al performed whole-genome sequencing on tumor samples and matched normals from 12 children with ETP-ALL. Tumor samples from two WGS cases also underwent transcriptome sequencing (RNA-seq). To extend their findings, the authors assembled a recurrence cohort of 94 T-cell ALL cases (52 ETP and 42 non-ETP). Three of the ETP samples in the extension cohort also underwent exome sequencing. On average, the authors 1,140 somatic mutations, including 154 that altered protein sequence, and 12 somatic structural rearrangements. More than half of the missense mutations were predicted to be deleterious, suggesting an enrichment for driver mutations involved in leukemogenesis. Notably, 51% of the validated SVs had breakpoints in protein-coding genes, including several with roles in hematopoiesis or leukemogenesis.

Genetic Architecture of ETP-ALL

Mutation discovery in the WGS cohort followed by recurrence testing in the extension cohort enabled the authors to identify several genetic patterns in ETP-ALL.

Lesion Type Pathway Frequency Genes
Activating mutations Cytokine receptor and RAS signaling 67% NRAS, KRAS, FLT3, IL7R, JAK3, SH2B3, BRAF
Inactivating lesions Hematopoietic development 58% GATA3, ETV6, RUNX1, IKZF1, EP300
Inactivating lesions Histone modification 48% EZH2, EED, SUZ12, SETD2, EP300

ETP-ALL is a stem-cell leukemia

A detailed comparison of gene expression signatures between ETP ALL tumors and and normal human hematopoietic progenitor cells revealed a somewhat surprising finding: ETP-ALL expression patterns were less consistent with early T-cell precursors, as might have been expected, but more similar to the expression profile of normal hematopoietic stem cells and granulocyte macrophage precursors. They were also enriched for genes expressed in leukemic stem cells of poor-prognosis AML. The evidence from this study suggests that the genetic alterations in ETP ALL cause “gross maturational arrest” resulting in a poorly-differentiated, stem-cell-like leukemia. This observation raises the possibility that treatment regimens for AML, such as high-dose cytarabine, may be beneficial in treating this deadly malignancy.

References
Zhang, J., Ding, L., Holmfeldt, L., Wu, G., Heatley, S., Payne-Turner, D., Easton, J., Chen, X., Wang, J., Rusch, M., Lu, C., Chen, S., Wei, L., Collins-Underwood, J., Ma, J., Roberts, K., Pounds, S., Ulyanov, A., Becksfort, J., Gupta, P., Huether, R., Kriwacki, R., Parker, M., McGoldrick, D., Zhao, D., Alford, D., Espy, S., Bobba, K., Song, G., Pei, D., Cheng, C., Roberts, S., Barbato, M., Campana, D., Coustan-Smith, E., Shurtleff, S., Raimondi, S., Kleppe, M., Cools, J., Shimano, K., Hermiston, M., Doulatov, S., Eppert, K., Laurenti, E., Notta, F., Dick, J., Basso, G., Hunger, S., Loh, M., Devidas, M., Wood, B., Winter, S., Dunsmore, K., Fulton, R., Fulton, L., Hong, X., Harris, C., Dooling, D., Ochoa, K., Johnson, K., Obenauer, J., Evans, W., Pui, C., Naeve, C., Ley, T., Mardis, E., Wilson, R., Downing, J., & Mullighan, C. (2012). The genetic basis of early T-cell precursor acute lymphoblastic leukaemia Nature, 481 (7380), 157-163 DOI: 10.1038/nature10725

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