Hematopoiesis and Hematological Malignancies
Members in the Hematopoiesis and Hematological Malignancies Program aim to understand the molecular basis of normal and aberrant hematopoiesis to improve the diagnosis and treatment of hematological diseases. Over the past year, Program members have produced over 60 published articles, many in high-impact journals; 26% of publications are intraprogrammatic and 15% interprogrammatic. Publication highlights that emphasize important research themes are summarized below.
CALM-AF10 alters the phenotype of leukemia in mice
The CALM gene, whose product is involved in clathrin-mediated endocytosis, has been identified in two recurring chromosomal translocations. Fusion proteins resulting from these translocations may contribute to the development of cancer. Led by Michelle M. Le Beau, PhD, researchers including John Anastasi, MD, have shown that the clathrin-binding domain of CALM-AF10 alters the phenotype of myeloid neosplasms in mice. Using a mouse model, they observed that exclusion of the C-terminal portion of CALM, which is required for optimal binding to clathrin, resulted in the development of a myeloproliferative disease, whereas inclusion of this domain led to the development of acute myeloid leukemia and changes in gene expression of several cancer-related genes. The study also showed that CALM-AF10 can homo-oligomerize. While these results suggest that endocytosis is not a major contributing factor to the development of leukemia, the oligomerization of CLAM-AF10 with other proteins may be an influencing factor. (Stoddart et al., Oncogene 31: 494-506, 2012)
This work was supported by grant number GM038093 from the National Institutes of Health, as well as the Leukemia and Lymphoma Society, the Cancer Research Foundation, and the Lauri Strauss Leukemia Foundation.
Statistical analysis yields predictors of transplant matches
Unrelated hematopoietic cell transplantation (HCT) is a treatment option for patients with hematological malignancies who do not have a human leukocyte antigen (HLA)-identical sibling. HLA mismatches have significant effects on graft survival and the development of graft-versus-host disease. Susana Marino, MD, PhD, and colleagues used a novel statistical methodology, known as random forest analysis, to evaluate the largest currently available dataset of hematopoietic cell transplants to identify HLA class I amino acid substitutions associated with reduced survival. They confirmed 13 previously identified HLA amino acid substitutions and identified 20 additional novel amino acid substitutions that are predictors of survival 100 days after transplant. These findings could improve donor selection for patients who lack HLA matched donors. (Marino et al., Bone Marrow Transplant 47:217-26, 2012)
This work was supported by the UCCCC.
PIM1 and BCL6 cooperate to promote the development of lymphoma
The development of lymphoma evolves as a result of multiple genetic alterations. Using retroviral insertional mutagenesis, Beverly Baron, MD, and colleagues including John Anastasi, MD, and Michael Thirman, MD, identified PIM1, a gene that encodes a serine/thereonine kinase, as the most frequently recurring cooperating gene in murine BCL6-associated lymphomas. Immunohistochemical staining of human B- and T-cell lymphomas revealed concurrent expression of BCL6 and PIM1, confirming the relevance of this finding to human lymphomagenesis. These findings indicate that PIM1 kinase inhibition may be a promising therapy for BCL6/PIM1-positive human lymphomas. (Baron et al., Proc Natl Acad Sci 109:5735, 2012)
This work was supported by the Department of Pathology at the University of Chicago, University of Chicago Cancer Center Support Grant P30 CA014599, and Hematology Research Funds at the University of Chicago donated by S. Samsky and E. Lanzl.
Single microRNA targets both oncogenes and tumor suppressors in MLL-rearranged leukemia
A study published in Nature Communications showed that a specific microRNA (miRNA), miR-196b, plays a dual role in the development of leukemia by repressing the expression of both oncogenes and tumor-suppressor genes, contrary to the current paradigm that miRNAs selectively target one or the other group of genes. Researchers suggest that the repression of tumor-suppressor genes, such as FAS, contributes to the generally poor prognosis of mixed lineage leukemia (MLL)-rearranged leukemia. These new findings indicate the need to update our present concepts about the role of miRNAs in cancer development. Jianjun Chen, PhD, James Vardiman, MD, and Michelle M. Le Beau, PhD, were involved with the study. (Li et al., Nat Commun 3:688, 2012)
This work was supported in part by the National Institutes of Health (NIH) R01 grant CA127277, American Cancer Society (ACS) Research Scholar grant, LLS Special Fellowship, Gabrielle's Angel Foundation for Cancer Research, Leukemia and Lymphoma Society (LLS) Translational Research Grant, Fidelity Foundation, NIH R01 CA118319 Sub-Award, R01 HL95896, HL087188, Intramural Research Program of National Human Genome Research Institute, NIH, NIH P01 CA40046, and P30 CA014599 Cancer Center Support Grant.