C-Rel Is A Transcriptional Target of Mesoderm Inducer In Xenopus Like 1 (Mixl1)

<p>MIXL1, an evolutionarily conserved, paired-type homeobox transcription factor induced by BMP4/TGFb signaling, is a critical regulator of embryonic and adult hematopoiesis. Several lines of evidence implicate MIXL1 in hematopoietic transformation: (i) Aberrant MIXL1 expression is seen in human CML ( Chronic Myelogenous Leukemia) in blast crisis, AML (Acute myelogenous leukemia), B cell lymphomas and pediatric ALL (Acute lymphocytic leukemia). (ii) Retroviral transduction of Mixl1 induces AML in murine models. Nonetheless, mechanisms underlying MIXL1 mediated proliferative, survival advantages are unknown.</p> <p>The goal of my studies is to understand if and how aberrant MIXL1 expression contributes to leukemogenesis. As a first step, I sought to determine transcriptional targets of MIXL1. Using MIXL1 overexpression lines established in the human myelomonocytic leukemia cell line, U937, I performed global chromatin immunoprecipitation coupled sequencing (ChIP-Seq), expression profiling studies I identified several putative targets. Of these, the proto-oncogene c-REL was an important target. Both ectopically expressed and endogenous MIXL1 bound <em>REL</em> promoters in myelogenous leukemia cells. Furthermore, cREL was induced under MIXL1 over-expression conditions in the leukemic cell line U937. Targeted shRNA mediated knockdown of endogenous MIXL1 in AML cell lines down regulated <em>REL</em> expression.</p> <p>c-REL the cellular homolog of the viral oncogene v-rel encoded by the oncogenic reticuloendotheliosis retrovirus, is a member of the Nf-κB/Rel gene family. c-REL transcriptionally activates proliferation and immune response and represses apoptosis through upregulation of anti-apoptotic genes. c-REL plays a critical role in hematopoietic differentiation. It is required for B-cell differentiation, and dendritic cells to activate T cells. In the myeloid lineage, c-REL is critical for macrophage mediated innate immunity. My findings suggest that transcriptional up regulation of <em>REL</em> by MIXL1, therefore would promote survival or proliferation through activation of the Nf-κB pathway in AML cells. Consistent with these established activities of c-REL, expression of two anti-apoptotic genes BCL2A1 and BCL2L1 increased under MIXL1 over-expression conditions and decreased under conditions of MIXL1 knockdown by targeted shRNA in U937 cells. In summary, my studies identify c-REL to be a novel mediator of MIXL1-induced survival signals in leukemia.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2013

Author dc:creator

• Raymond, Aaron C

Contributors dc:contributor

• Lalitha Nagarajan, PhD
• Richard Behringer, PhD
• Yasuhide Furuta, PhD

• MIXL1
• c-REL
• NF-kappaB
• BCL2A1
• BCL2L1
• AML
• BMP
• Medicine and Health Sciences
• Molecular Genetics

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/415

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1454