Genomics of LGL leukemia and select other rare leukemia/lymphomas

Abstract

Genomic analysis of cancer offers the hope of identifying new treatments or aiding in the selection of existing treatments. Rare leukemias pose additional challenges in this regard as samples may be hard to acquire and when found the underlying pathway may not be attractive to drug development since so few individuals are affected. In this case, it can be useful to identify common mutational overlap among subsets of rare leukemias to increase the number of individuals that may benefit from a targeted therapy. This chapter examines the current mutational landscape of large granular lymphocyte (LGL) leukemia with a focus on STAT3 mutations, the most common mutation in LGL leukemia to date. We examined the linkage between these mutations and autoimmune symptoms and disorders, in cases of obvious and suspected LGL leukemia. We then summarized and compared mutations in a set of other rare leukemias that also have JAK/STAT signaling pathway activation brought about by genomic changes. These include T-cell acute lymphoblastic leukemia (T-ALL), T-cell prolymphocytic leukemia (T-PLL), cutaneous T-cell lymphoma (CTCL), select peripheral T-cell lymphoma (PTCL), and adult T-cell leukemia/lymphoma (ATLL). Though STAT3 activation is common in these leukemias, the way in which it is achieved, such as the activating cytokine pathway and/or the co-mutational background, is quite diverse.

Keywords: ATLL; CTCL; JAK/STAT; LGL; PTCL; STAT3; T-ALL; T-PLL.

Figure 1.. Somatic mutation frequencies of Homo sapiens STAT3 in hematological malignancies and comparison of STAT3 and STAT5B amino acid sequences.

STAT3 mutations specific to hematopoietic and lymphoid tissue were downloaded from COSMIC and cBio portal (STAT3 accession # NM_139276) and shown as lollipop plots. Domains are N-terminal, coiled-coil, DNA binding, linker, Src homology 2 (SH2), and transactivation (TA) (A-D). STAT3 mutation frequency is listed for (A) LGL leukemia (B) ATL, MDS, and NK/T lymphoma, and (C) all other hematological malignancies. Green, black, red, and pink circles indicate missense, truncation, in-frame, or other mutations, respectively. (D) STAT3 (alpha isoform) and STAT5B Homo sapiens amino acid sequences were retrieved from the NCBI Protein Database (accession # NP_644805 for STAT3, NP_036580 for STAT5B). The sequences were aligned using Clustal Omega, The C-terminal sequence including the SH2 and TA domains are shown. Asterisks indicate a fully-conserved amino acid at a position, while colons and periods indicate conserved and semi-conserved substitutions, respectively. STAT3 and STAT5B somatic mutations are annotated in red and blue, respectively. In two cases (Y640F and N647I) the STAT3 mutation creates the innate STAT5B amino acid.

Figure 2.. Rare leukemia cell lineage highlighting genomic differences from normal cell counterparts.

A simplified T-cell hematopoietic lineage is shown, along with annotations indicating which cells represent the normal counterpart of a particular leukemia. Within each cancer cell, genomic aberrations that are known to cause increased JAK/STAT signaling along with other known mutations or gene rearrangements are listed.