Primary or idiopathic myelofibrosis (PMF) is the most lethal type of myeloproliferative neoplasm (MPN) and is characterized by an accumulation of fibrous tissue in the bone marrow and extramedullary hematopoiesis. Among patients with PMF, the outcomes are poorest for those with advanced-stage disease that has evolved into acute myeloid leukemia (AML). Outcomes are vastly improved if PMF is treated at its early pre-fibrotic stage but diagnosis of pre-fibrotic PMF is profoundly challenging. No mutation that is specific to PMF has been identified. Abnormal megakaryocyte growth and anemia are predominant features of early-stage PMF, but are also seen in some other types of hematologic diseases in which fibrosis and AML evolve less frequently. Our goal is to determine the mechanisms that promote the progression of PMF and its transformation to AML. We have extensively investigated the mechanisms of transcription factors encoded by homeobox genes in controlling cell differentiation, oncogenic signaling and tumor-stroma interactions. This exploratory study is a new direction that focuses on the transcription factor DLX4 in PMF. Based on our preliminary studies, we hypothesize that DLX4 promotes the progression of PMF and increases the propensity for AML evolution.
In Aim 1, we will determine whether DLX4 induces the histopathologic features of PMF and AML evolution in mouse engraftment models.
In Aim 2, we will determine the relationship between DLX4 expression, progression of PMF and AML evolution in a retrospective study of clinical specimens. If our study is successful, DLX4 could be a potential biomarker for distinguishing early-stage PMF from other morphologically similar but less lethal diseases and for assessing the risk of AML evolution in patients diagnosed with PMF.

Public Health Relevance

Primary myelofibrosis is a type of myeloproliferative neoplasm that evolves into acute myeloid leukemia in a subset of patients. This proposal investigates the biological and clinical significance of a transcription factor in promoting the progression of primary myelofibrosis and its transformation to acute myeloid leukemia. These studies will provide new insights for improving diagnosis of primary myelofibrosis at its early stage and for evaluating the risk of leukemic evolution.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA195665-02
Application #
9231413
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Mufson, R Allan
Project Start
2016-03-01
Project End
2018-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
2
Fiscal Year
2017
Total Cost
$156,600
Indirect Cost
$58,725
Name
University of Texas MD Anderson Cancer Center
Department
Microbiology/Immun/Virology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030