Elucidating altered transcriptional programs

Natural killer (NK) T (NKT) cells are a conserved population of innate-like T cells that express CD1d-restricted semi-invariant αβ T-cell receptors (TCRs), using mostly the Vα14-Jα18 chain in mouse (Vα24-Jα18 in human) combined with variable Vβ8, Vβ7, and Vβ2 (Vβ11 in human) chains, which confer recognition of conserved self and foreign lipids (1 phenotype along with receptors of the NK cell lineage.

The innate-like effector functions of NKT cells are illustrated by the cells’ ability to promptly secrete large quantities of both IL-4 and IFN-γ either after TCR activation or on exposure to tissue- and antigen-presenting cell-derived cytokines, such as IL-25 IL-33 and IL-12 IL-18, respectively.

Constellation Pharmaceuticals, Cambridge, Massachusetts, USA. Address correspondence to: Alexandros Tzatsos or Nabeel Bardeesy, 185 Cambridge Street, Boston, Massachusetts 02114, USA. (C–F) IHC staining for KDM2B in human pancreatic tissues.

Phone: 617.643.3156; Fax: 617.643.3170; E-mail: Tzatsos. (C) Normal (N.) adult pancreas was negative for KDM2B.

This work establishes that T-ALL cells possess the same general motifs of transcriptional circuitry that were identified earlier in stem cells.

To elucidate the mechanisms underlying this unique property of PLZF, we performed Ch IP-seq and microarray analysis of NKT cells and PLZF-transgenic T cells, which revealed direct regulation of effector genes and of T-helper–specific transcription factors. Phone: 617.643.2579; Fax: 617.643.3170; E-mail: Bardeesy. Phone: 617.643.3156; Fax: 617.643.3170; E-mail: Tzatsos. (A) Heat map of quantitative RT-PCR data showing relative expression of HDM family members in human PDAC cell lines versus HPDE cells. (B) KDM2B transcript levels in a series of human PDAC specimens compared with normal pancreatic tissue, determined by RNA-seq (samples from MGH tumor bank). Address correspondence to: Alexandros Tzatsos or Nabeel Bardeesy, 185 Cambridge Street, Boston, Massachusetts 02114, USA. Among these highly upregulated HDMs, the H3K36 demethylase KDM2B has been implicated in bypass of cellular senescence, induction of pluripotency, and tumorigenesis and was selected for further characterization in PDAC.As a physician scientist, I am particularly motivated by work that has the potential to improve public health, by advancing understanding of cancer for the eventual development of improved therapeutics.I hope to translate the knowledge gained from the experimental studies into effective therapy.

Leave a Reply