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You are Here: LUHS > CBCC >Oncology Institute > Research Programs > Hematologic Malignancy |
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Hematologic Malignancy Program |
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Programmatic Objectives:
The general objective of the Hematologic
Malignancy Program is to understand the
process of oncogenesis in leukemias and
lymphomas, and utilize this knowledge to
innovate and improve diagnostic and
therapeutic strategies. The Hematologic
Malignancy Program therefore combines
the strong molecular oncology expertise
of this basic research group with the
recognized clinical investigative skills
of this clinical research group.
Diaz’s research activities focus on the mechanisms that lead to leukemia development by mutant proteins that arise from mutations of the MLL gene. This is primarily through the function of the normal MLL protein, and how the mutant MLL-fusion proteins differ from the normal MLL in their function. Since these proteins regulate the expression of a subset of genes that are master regulators of cell proliferation and differentiation during development, studies are directed toward the effect of MLL mutations on the development of blood cells, and especially on the transition from blood stem cells to the different lineages of differentiated blood cells. This transition is altered in all leukemias, and understanding how MLL mutants affect it may allow understanding of a crucial initial step for leukemogenesis in general. This may be important not only to find appropriate targets for new and more specific therapies, but also to conceive new ways to reduce the incidence of leukemia by preventive measures. MLL is very similar to a protein called trithorax, found in the fruit fly. As there is a well-developed understanding of how trithorax functions in controlling development in the fruit fly, fruit fly cells are used to understand how trithorax regulate genes involved in development, and these results are extrapolated to the human MLL function. Mouse blood stem cells infected with viruses that can express mutant forms of MLL are used to study the role of different parts of the MLL molecule, and of other proteins or RNA molecules that interact with MLL, in leukemogenesis. The infected cells can be grown in vitro to observe how they differentiate into blood cell colonies, or can be injected in live mice to observe if they give rise to leukemia. Diaz representative publications
Andrew Dingwall, PhD
In most living cells, chromosomes are
formed from highly condensed DNA and
basic proteins that function to compact
the chromosomes into a structure called
chromatin. Dr. Dingwall's research is
focused on understanding the multitude
of critically important roles chromatin
structure plays in normal development
and disease. In particular, his lab
studies a highly conserved group of
proteins that form a complex whose main
function is to regulate gene expression
through direct effects on chromatin
structure. As this complex is quite
large and composed of at least eight
different proteins, research efforts are
targeted at understanding how each
subunit contributes to the various
intricate functions of the complex in
regulating tissue-specific gene
expression during organismal
development, as well as tumor cells. For
example, when individual components of
this complex are missing or mutated,
certain cells lose the ability to
properly control their fates and growth,
leading to a variety of diseases
including aggressive cancers. As part of
the Hematologic Malignancies Program
within the Oncology Institute, the
Dingwall lab is focused on understanding
the molecular, genetic and epigenetic
mechanisms involving chromatin
remodeling that govern normal animal
development, as well as several types of
leukemia, lymphoma and aggressive
soft-tissue cancers. Investigative
approaches utilize a systems biology
perspective, incorporating model
organism (Drosophila melanogaster)
genetics and biochemistry, cell biology,
fly and mammalian cell culture, as well
as microarray-based gene expression
profiling technologies.
Charles Hemenway, MD, PhD
Among the more
commonly recurring chromosomal
translocations in acute lymphoblastic
leukemia (ALL) is t(4;11)(q21;q23). As a
consequence of this translocation, the
MLL gene at 11q23 is fused to AF4 at
4q21 and a “chimeric” MLL-AF4 protein is
expressed in leukemia cells. The t(4;11)
translocation is present in 5-10% of
older children and adults with ALL, and,
remarkably, this abnormality is detected
in more than 50% of infants with ALL.
Unfortunately, in both children and
adults, t(4;11) ALL has a particularly
poor prognosis. However, it may be
possible to exploit the t(4;11)
translocation to therapeutic advantage.
We have found that another MLL fusion
protein, AF9, interacts with AF4 through
a protein-binding domain that is
retained in MLL-AF4 chimeras. Moreover,
we have generated a small synthetic
peptide that disrupts AF4-AF9 protein
complexes. This peptide, PFWT, is a
potent inducer of cell death in t(4;11)
leukemia cell lines, but the peptide
does not inhibit the colony forming
potential of hematopoietic progenitor
cells. PFWT, or other small molecules
that block AF4-AF9 protein interactions,
represent a new and potentially
effective venue for the treatment of
t(4;11) leukemia.
Hemenway
Representative Publications Ameet Kini, MD, PhD Department of Pathology Dr. Kini’s laboratory examines the role of angiogenesis in hematologic malignancies. The notion that angiogenesis is important in cancer was first popularized by Dr. Judah Folkman in 1971. Since then numerous studies have shown that growth of tumors beyond a diameter of about 2mm requires angiogenesis. Anti-angiogenic strategies have been successfully used in mouse models to eliminate tumors. A large number of clinical trials are now taking place to assess different anti-angiogenic drugs in humans. Meanwhile, the role of angiogenesis in leukemias was ignored because there did not appear to be any obvious need for angiogenesis in these "blood cancers". However, numerous recent studies have demonstrated increased bone marrow angiogenesis in leukemias, and this bone marrow angiogenesis may be required for the proliferation of the leukemic cells. In addition, it appears that the "angiogenic" factors play an important role in cell survival and apoptosis, through paracrine or autocrine loops. Dr. Kini’s lab focuses on the role of vascular endothelial growth factor (VEGF) and other angiogenic factors in acute promyelocytic leukemia, a subtype of acute myeloid leukemia. This research may lead to novel, relatively non-toxic, anti-angiogenic therapies for hematologic malignancies.
Kini
representative publications
Nancy Zeleznik-Le, PhD
Dr. Zeleznik-Le’s research interest is focused on the MLL protein, and on MLL fusion proteins that cause leukemia. MLL is involved in the proper maintenance of expression of downstream target genes, including genes of the HOX cluster. How MLL functions to help maintain proper expression of target genes is not well understood, but it is thought to involve epigenetic mechanisms acting at the level of chromatin. One focus of her work is to identify chromatin changes that are mediated by MLL and MLL fusion proteins. This also includes studies to understand how proteins that interact with MLL compete and /or synergize to mediate these effects, and the role of post-translational modifications of MLL on its function. Another main focus of her research utilizes in vitro and in vivo murine models of MLL leukemia to dissect critical functions required for immortalization and leukemogenesis. Questions addressed concern hematopoietic cell lineage commitment, and specificity of MLL and partner gene functional domains for immortalization capability. Dr. Zeleznik-Le has been involved in the cloning of several MLL fusion genes from patient leukemia samples, including the MLL-CBP fusion. She has developed murine models of MLL leukemia that recapitulate the human disease. Her laboratory has identified proteins that interact with MLL, including those with chromatin modifying capability.Jiwang Zhang, MD, PhD Department of Pathology Stem cells are a key subset of cells in the body that function as ancestor cells to produce a variety of types of functionally specialized mature cells in a given tissue, while at the same time maintaining the capacity of self-renewal. Self-renewal of stem cells is a process of continuous division to reproduce themselves. This process is controlled by intrinsic genetic pathways that are subject to regulation by extrinsic signals from the microenvironment in which stem cells reside. Stem cell development is a complex process and is maintained precisely in balance among different cell events including self-renewal, differentiation, apoptosis, and migration. Breaking this balance tends to lead to either lack of or uncontrolled cell growth, thereby developing into a variety of diseases including tissue defects and cancers. Hematopoietic stem cells (HSCs) play essential roles in hematopoietic tissue homeostasis and regeneration. Leukemia stem cells (LSCs) are the subset of malignant cells in leukemia patients which are the initiators of leukemia development and are also the resources of leukemia relapse. Like normal stem cells, LSCs have self-renewal capacity. LSCs derived either from normal HSCs that obtained malignant properties without losing self-renewal ability or mutant progenitors which gained the self-renewal feature. Therefore, LSCs are the key targets for clinical leukemia therapy.The overall objectives of our research are: 1. to investigate the cellular and molecular mechanisms that regulate bone marrow HSC self-renewal, proliferation and differentiation and the interaction between stem cells and their microenvironment; 2. to investigate the LSC and leukemia development by using genetically modulated mouse models. This study is important to enhance our understanding of the nature of stem cells and leukemia development. It will help to identify cellular components and molecules that are important for in vitro expansion of HSC, which could be used for clinical therapies. Additionally, it will provide insights of the difference in molecular regulations of LSC and normal HSC which would lead to the discovery of specific targets for destroying the LSCs without affecting the normal HSCs.
Zhang Representative Publications
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Last reviewed:
Aug. 28, 2008 |
