Limits...
Histone acetyltransferases and histone deacetylases in B- and T-cell development, physiology and malignancy.

Haery L, Thompson RC, Gilmore TD - Genes Cancer (2015)

Bottom Line: The signaling pathways and gene expression patterns that give rise to these developmental processes are coordinated, in part, by two opposing classes of broad-based enzymatic regulators: histone acetyltransferases (HATs) and histone deacetylases (HDACs).HATs and HDACs can modulate gene transcription by altering histone acetylation to modify chromatin structure, and by regulating the activity of non-histone substrates, including an array of immune-cell transcription factors.In addition to their role in normal B and T cells, dysregulation of HAT and HDAC activity is associated with a variety of B- and T-cell malignancies.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Boston University, Boston, MA, USA.

ABSTRACT
The development of B and T cells from hematopoietic precursors and the regulation of the functions of these immune cells are complex processes that involve highly regulated signaling pathways and transcriptional control. The signaling pathways and gene expression patterns that give rise to these developmental processes are coordinated, in part, by two opposing classes of broad-based enzymatic regulators: histone acetyltransferases (HATs) and histone deacetylases (HDACs). HATs and HDACs can modulate gene transcription by altering histone acetylation to modify chromatin structure, and by regulating the activity of non-histone substrates, including an array of immune-cell transcription factors. In addition to their role in normal B and T cells, dysregulation of HAT and HDAC activity is associated with a variety of B- and T-cell malignancies. In this review, we describe the roles of HATs and HDACs in normal B- and T-cell physiology, describe mutations and dysregulation of HATs and HDACs that are implicated lymphoma and leukemia, and discuss HAT and HDAC inhibitors that have been explored as treatment options for leukemias and lymphomas.

No MeSH data available.


Related in: MedlinePlus

CBP/p300 mutations reported in CCLE in B- and T-cell cancer cell linesSchematic diagram of the CBP/p300 proteins with conserved domains indicated in the shaded regions as follows: cysteine/histidine domain (CH), KIX domain, bromodomain (Br), acetyltransferase domain (KAT). Symbol shapes designate types of mutations as follows: missense (circle); nonsense (triangle); and frameshift, splice site, or deletion (square). Symbol color indicates the disease type: DLBCL (red); Hodgkin's lymphoma (blue); T-cell leukemia (acute lymphoblastic or anaplastic large cell) (green); plasma cell myeloma (yellow); acute lymphoblastic B-cell leukemia (purple); B-cell lymphoma unspecified (black); and Burkitt's lymphoma (white). CBP mutations are (in order, left to right) Q170*, M395T, L470fs, A620V, Q790*, P901L, P928A, P975L, S1108L, K1203 splice, E1238*, T1332I, R1360*, S1432P, D1435E, F1440L, R1446L, Q1491K, S1680del, and S1687P. p300 mutations are Q160*, M165I, V279I, S281T, L415P, M514V, R728W, E1011*, E1160V, A1268V, R1391 splice, H1415P, G1506V, L1520V, K1546fs, R1627W, S1650F, R1773W, Q1904P, A2259T, P2358L, P2367L.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4482241&req=5

Figure 2: CBP/p300 mutations reported in CCLE in B- and T-cell cancer cell linesSchematic diagram of the CBP/p300 proteins with conserved domains indicated in the shaded regions as follows: cysteine/histidine domain (CH), KIX domain, bromodomain (Br), acetyltransferase domain (KAT). Symbol shapes designate types of mutations as follows: missense (circle); nonsense (triangle); and frameshift, splice site, or deletion (square). Symbol color indicates the disease type: DLBCL (red); Hodgkin's lymphoma (blue); T-cell leukemia (acute lymphoblastic or anaplastic large cell) (green); plasma cell myeloma (yellow); acute lymphoblastic B-cell leukemia (purple); B-cell lymphoma unspecified (black); and Burkitt's lymphoma (white). CBP mutations are (in order, left to right) Q170*, M395T, L470fs, A620V, Q790*, P901L, P928A, P975L, S1108L, K1203 splice, E1238*, T1332I, R1360*, S1432P, D1435E, F1440L, R1446L, Q1491K, S1680del, and S1687P. p300 mutations are Q160*, M165I, V279I, S281T, L415P, M514V, R728W, E1011*, E1160V, A1268V, R1391 splice, H1415P, G1506V, L1520V, K1546fs, R1627W, S1650F, R1773W, Q1904P, A2259T, P2358L, P2367L.

Mentions: Although chromosomal translocations involving p300, CBP and MYST are well-documented in acute myeloid leukemia [90], they have not been found in B- and T-cell malignancies. However, other types of HAT gene mutations are common in certain types of B- and T-cell cancers. Namely, the genes encoding CBP and p300 harbor point mutations or deletions in approximately 20–40% of DLBCL [88, 91, 92], about 70% of follicular lymphomas (FL) [93], and less frequently in T-cell leukemia, acute lymphoblastic leukemia (ALL) and myelodysplastic syndrome [94, 95]. The TIP60 gene frequently suffers mono-allelic loss and reduced expressed in several types of B-cell lymphoma [95]. Moreover, our analysis of the Cancer Cell Line Encyclopedia (CCLE) database [96] finds that mutations in CBP/p300 and other HATs (especially MORF) are common in a variety of B- and T-cell cancer cell lines (Table 3). With CBP and p300, the majority of these lymphoma mutations occur within or near the HAT domain or introduce frame-shifts or stop codons N-terminal to the HAT domain (see Figure 2). Thus, many of the CBP/p300 mutations found in DLBCL and FL are predicted to reduce acetyltransferase activity [88]. Indeed, several of these point mutations have been demonstrated to impair the affinity of CBP for acetyl-CoA and consequently compromise the ability of CBP to acetylate the TFs BCL6 and p53 [88]. Of note, acetylation of BCL6 decreases its gene repressing activity, whereas acetylation of p53 is required for its gene activation function (Table 2) [50, 97]. Thus, DLBCL cells with HAT gene mutations have higher levels of active BCL6 and lower levels of active p53 [88], consistent with decreased acetylation being associated with increased tumor cell growth.


Histone acetyltransferases and histone deacetylases in B- and T-cell development, physiology and malignancy.

Haery L, Thompson RC, Gilmore TD - Genes Cancer (2015)

CBP/p300 mutations reported in CCLE in B- and T-cell cancer cell linesSchematic diagram of the CBP/p300 proteins with conserved domains indicated in the shaded regions as follows: cysteine/histidine domain (CH), KIX domain, bromodomain (Br), acetyltransferase domain (KAT). Symbol shapes designate types of mutations as follows: missense (circle); nonsense (triangle); and frameshift, splice site, or deletion (square). Symbol color indicates the disease type: DLBCL (red); Hodgkin's lymphoma (blue); T-cell leukemia (acute lymphoblastic or anaplastic large cell) (green); plasma cell myeloma (yellow); acute lymphoblastic B-cell leukemia (purple); B-cell lymphoma unspecified (black); and Burkitt's lymphoma (white). CBP mutations are (in order, left to right) Q170*, M395T, L470fs, A620V, Q790*, P901L, P928A, P975L, S1108L, K1203 splice, E1238*, T1332I, R1360*, S1432P, D1435E, F1440L, R1446L, Q1491K, S1680del, and S1687P. p300 mutations are Q160*, M165I, V279I, S281T, L415P, M514V, R728W, E1011*, E1160V, A1268V, R1391 splice, H1415P, G1506V, L1520V, K1546fs, R1627W, S1650F, R1773W, Q1904P, A2259T, P2358L, P2367L.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4482241&req=5

Figure 2: CBP/p300 mutations reported in CCLE in B- and T-cell cancer cell linesSchematic diagram of the CBP/p300 proteins with conserved domains indicated in the shaded regions as follows: cysteine/histidine domain (CH), KIX domain, bromodomain (Br), acetyltransferase domain (KAT). Symbol shapes designate types of mutations as follows: missense (circle); nonsense (triangle); and frameshift, splice site, or deletion (square). Symbol color indicates the disease type: DLBCL (red); Hodgkin's lymphoma (blue); T-cell leukemia (acute lymphoblastic or anaplastic large cell) (green); plasma cell myeloma (yellow); acute lymphoblastic B-cell leukemia (purple); B-cell lymphoma unspecified (black); and Burkitt's lymphoma (white). CBP mutations are (in order, left to right) Q170*, M395T, L470fs, A620V, Q790*, P901L, P928A, P975L, S1108L, K1203 splice, E1238*, T1332I, R1360*, S1432P, D1435E, F1440L, R1446L, Q1491K, S1680del, and S1687P. p300 mutations are Q160*, M165I, V279I, S281T, L415P, M514V, R728W, E1011*, E1160V, A1268V, R1391 splice, H1415P, G1506V, L1520V, K1546fs, R1627W, S1650F, R1773W, Q1904P, A2259T, P2358L, P2367L.
Mentions: Although chromosomal translocations involving p300, CBP and MYST are well-documented in acute myeloid leukemia [90], they have not been found in B- and T-cell malignancies. However, other types of HAT gene mutations are common in certain types of B- and T-cell cancers. Namely, the genes encoding CBP and p300 harbor point mutations or deletions in approximately 20–40% of DLBCL [88, 91, 92], about 70% of follicular lymphomas (FL) [93], and less frequently in T-cell leukemia, acute lymphoblastic leukemia (ALL) and myelodysplastic syndrome [94, 95]. The TIP60 gene frequently suffers mono-allelic loss and reduced expressed in several types of B-cell lymphoma [95]. Moreover, our analysis of the Cancer Cell Line Encyclopedia (CCLE) database [96] finds that mutations in CBP/p300 and other HATs (especially MORF) are common in a variety of B- and T-cell cancer cell lines (Table 3). With CBP and p300, the majority of these lymphoma mutations occur within or near the HAT domain or introduce frame-shifts or stop codons N-terminal to the HAT domain (see Figure 2). Thus, many of the CBP/p300 mutations found in DLBCL and FL are predicted to reduce acetyltransferase activity [88]. Indeed, several of these point mutations have been demonstrated to impair the affinity of CBP for acetyl-CoA and consequently compromise the ability of CBP to acetylate the TFs BCL6 and p53 [88]. Of note, acetylation of BCL6 decreases its gene repressing activity, whereas acetylation of p53 is required for its gene activation function (Table 2) [50, 97]. Thus, DLBCL cells with HAT gene mutations have higher levels of active BCL6 and lower levels of active p53 [88], consistent with decreased acetylation being associated with increased tumor cell growth.

Bottom Line: The signaling pathways and gene expression patterns that give rise to these developmental processes are coordinated, in part, by two opposing classes of broad-based enzymatic regulators: histone acetyltransferases (HATs) and histone deacetylases (HDACs).HATs and HDACs can modulate gene transcription by altering histone acetylation to modify chromatin structure, and by regulating the activity of non-histone substrates, including an array of immune-cell transcription factors.In addition to their role in normal B and T cells, dysregulation of HAT and HDAC activity is associated with a variety of B- and T-cell malignancies.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Boston University, Boston, MA, USA.

ABSTRACT
The development of B and T cells from hematopoietic precursors and the regulation of the functions of these immune cells are complex processes that involve highly regulated signaling pathways and transcriptional control. The signaling pathways and gene expression patterns that give rise to these developmental processes are coordinated, in part, by two opposing classes of broad-based enzymatic regulators: histone acetyltransferases (HATs) and histone deacetylases (HDACs). HATs and HDACs can modulate gene transcription by altering histone acetylation to modify chromatin structure, and by regulating the activity of non-histone substrates, including an array of immune-cell transcription factors. In addition to their role in normal B and T cells, dysregulation of HAT and HDAC activity is associated with a variety of B- and T-cell malignancies. In this review, we describe the roles of HATs and HDACs in normal B- and T-cell physiology, describe mutations and dysregulation of HATs and HDACs that are implicated lymphoma and leukemia, and discuss HAT and HDAC inhibitors that have been explored as treatment options for leukemias and lymphomas.

No MeSH data available.


Related in: MedlinePlus