In:
Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 1663-1663
Abstract:
Abstract 1663 The current World Health Organization (WHO) classification of hematologic malignancies includes a number of entities defined by specific genetic abnormalities. Most known abnormalities result from chromosomal translocations and mutations involving genes encoding transcription factors or tyrosine kinases. We identified the activation of a novel palmitoyltransferase, ZDHHC14, through a chromosomal translocation, t(6;14)(q25;q32). This translocation was initially documented by three independent groups in two children and two adult patients with T/myeloid biphenotypic leukemia, a poorly differentiated form of acute leukemia with a single population of leukemic blasts co-expressing antigens of both T-lymphoid and myeloid lineages. Recently, we detected the same translocation in two additional patients with T/myeloid biphenotypic leukemia. Molecular characterization of the translocation breakpoints revealed the juxtaposition of a regulatory region downstream of BCL11B (at chromosome region 14q32) upstream of an uncharacterized gene, ZDHHC14 (at chromosome region 6q25), leading to transcriptional activation of the ZDHHC14. Notably, this regulatory region from 14q32 has been found to be responsible for transcriptional activation of a homeobox gene, TLX3, as a result of a cryptic translocation t(5;14)(q35;q32) in T-cell acute lymphoblastic leukemia. Our subsequent survey of ZDHHC14 protein levels in blasts from patients with various subtypes of acute myeloid leukemia (AML) showed that the protein was not detectable in AML patients with t(8;21), t(15;17), or inv(16), but was detected in AML patients with FLT3 mutations or with complex karyotypes, indicating a possible association of increased expression of this protein with unfavorable prognostic features of the disease. We also demonstrated that overexpression of ZDHHC14 could inhibit TPA-induced cellular differentiation of K562 cells. Interestingly, the Drosophila homolog of ZDHHC14 has been found to be a palmitoyltransferase regulating Fat signaling. Fat is a Drosophila tumor suppressor gene, encoding a large cadherin that regulates growth and a form of tissue organization. While the function of ZDHHC14 and the role of protein palmitoylation in mammalian hematopoiesis remain unknown, recent studies in neuronal development have demonstrated that palmitoylation regulates diverse aspects of protein trafficking. Our findings suggest that palmitoyltransferase plays a previously unappreciated role in hematopoiesis and that increased expression of ZDHHC14 may be associated with a primitive status of leukocytes. Further characterization of ZDHHC14 may broaden our knowledge of leukemogenesis, contribute to risk stratification of acute leukemia, and provide a novel therapeutic target. Disclosures: No relevant conflicts of interest to declare.
Type of Medium:
Online Resource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood.V116.21.1663.1663
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2010
detail.hit.zdb_id:
1468538-3
detail.hit.zdb_id:
80069-7
