The new Hematologic Oncology Translational (HOT) Laboratory located on the second floor of the James G. Cannon Research Building is under the direction of Belinda R. Avalos, MD and Jonathan M. Gerber, MD and staffed by senior scientists Lawrence Druhan, PhD and Sarah Baxter, PhD as well as three full-time technicians: Andrea Price, Amanda Patterson, and Jenna Sackenheim.
The overarching theme of the laboratory is to gain new insights into the pathogenesis of hematologic malignancies, particularly myeloid malignancies, to develop novel prognostic tools and more effective treatment approaches for patients with these disorders. In addition, the laboratory is investigating the influence of age, race, and ethnicity on disease biology.
The laboratory team has a wide array of state-of-the art instrumentation available for performing next generation sequencing (whole genome, exome, transcriptome, or methylome), gene expression microarrays, proteomic analyses, cytokine multiplex assays, cellular immunophenotyping and sorting by flow cytometry, immunomagnetic cell separation, and confocal immunofluorescence microscopy. The laboratory’s major areas of focus are:
Despite aggressive treatments that induce complete remission, the majority of patients with acute myelogenous leukemia (AML) will relapse and die of their disease. The high rate of disease recurrence suggests that current therapies kill the bulk of differentiated leukemic cells, but are ineffective at killing the key precursor cells responsible for disease initiation and relapse – the leukemia stem cells (LSCs). Recently, members of our laboratory identified a phenotypically distinct population of LSCs that could be distinguished from normal hematopoietic stem cells. Persistence of LSCs after achievement of complete remission was shown to have prognostic significance and correlate with relapse. Our current research efforts are focused on further characterizing LSCs at the cellular and molecular level through analysis of the LSC transcriptome and proteome to identify unique properties of LSCs that can be translated into clinical biomarkers and novel therapies that target LSCs but not normal hematopoietic stem cells. Similar studies to identify the stem cell origin of other malignant hematologic disorders are also underway. These studies are being done in conjunction with new clinical trials available to patients with hematologic malignancies at the Levine Cancer Institute. In addition, we are conducting collaborative studies with physicians at the Levine Children’s Hospital on pediatric leukemias and hematopoietic cell transplantation.
The hematologic malignancies are characterized by abnormalities in cell survival, proliferation, and differentiation. Knowledge regarding the native signaling pathways and proteins that regulate these processes is incomplete. Members of our laboratory previously demonstrated important roles for neutrophil elastase and leucine rich alpha-2 glycoprotein (LRG) in myeloid cell survival and differentiation. More recently, LRG was shown to promote angiogenesis and to be a biomarker for a variety of cancers and inflammatory conditions. Research studies in our laboratory are currently focused on elucidating the signaling pathways and proteins that interact with LRG to exert its pleiotropic activities to better understand how they are deregulated in myeloid disorders and inflammation.
Alterations in cell signaling due to mutations in growth factor receptors have been shown to play pivotal roles in a variety of cancers, and resulted in rapid development and clinical introduction of novel non-chemotherapeutic agents targeting mutant receptors. The granulocyte colony-stimulating factor receptor (G-CSFR), which critically regulates neutrophil production, has been shown to be mutated in some patients with AML and chronic neutrophilic leukemia. Members of our laboratory were the first to demonstrate that G-CSFR truncation mutations in patients with AML confer a clonal growth advantage by altering ligand-receptor internalization and degradation that leads to prolonged cell signaling and enhanced cell survival. Overexpression of an alternative G-CSFR isoform has also been reported in some patients with AML, and in children, was associated with higher relapse rates when G-CSF was administered after chemotherapy to shorten the period of neutropenia. Our current research efforts are directed at further analyzing G-CSFR isoforms and expanding G-CSFR mutational analyses to additional patients with leukemia and other malignant hematologic disorders to identify novel targets to exploit clinically.
Copelan EA, Grunwald MR, Ghosh N, Plesca D, Trivedi J, Avalos BR. Hematopoietic cell transplantation in chronic myeloid leukemia in the age of tyrosine kinase inhibitors. Discov Med. 2015 Mar;19(104):213-8. PMID: 25828525 or full free text
Copelan EA, Avalos BR, Ahn KW, Zhu X, Gale RP, Grunwald MR, Hamadani M, Hamilton BK, Hale GA, Marks DI, Waller EK, Savani BN, Costa LJ, Ramanathan M, Cahn JY, Khoury HJ, Weisdorf DJ, Inamoto Y, Kamble RT, Schouten HC, Wirk B, Litzow MR, Alijurf MD, van Besien KW, Ustun C, Bolwell BJ, Bredeson CN, Fasan O, Ghosh N, Horowitz MM, Arora M, Szer J, Loren AW, Alyea EP, Cortes J, Maziarz RT, Kalaycio ME, Saber W. Comparison of outcomes of allogeneic transplantation for chronic myeloid leukeumia with cyclophosphamide in combination with intravenous busulfan, oral busulfan, or total body irradiation. Biol Blood Marrow Transplant. 2015 Marh;21(3):552-8. PMID: 25528388 or PMCID: PMC4329042
Gerber JM, Gucwa JL, Esopi D, Gurel M, Haffner MC, Vala M, Nelson WG, Jones RJ, Yegnasubramanian S. Genome-wide comparison of the transcriptomes of highly enriched normal and chronic myeloid leukemia stem and progenitor cell populations. Oncotarget. 2013 May;4(5):715-28. PMID: 23651669 or PMCID: PMC3742832
Ghiaur G, Yegnasubramanian S, Perkins B, Gucwa JL, Gerber JM, Jones RJ. Regulation of human hematopoietic stem cell self-renewal by the microenvironment's control of retinoic acid signaling. Proc Natl Acad Sci U S A. 2013 Oct 1;110(40):16121-6. PMID: 24043786 or PMCID: PMC3791732
Gerber JM, Smith BD, Ngwang B, Zhang H, Vala MS, Morsberger L, Galkin S, Collector M, Perkins B, Levis MJ, Griffin CA, Sharkis SJ, Borowitz MJ, Karp JE, Jones RJ. A clinically relevant population of leukemic CD34+CD38- cells in acute myeloid leukemia. Blood 2012 Apr; 119(15):3571-7. PMID: 22262762 or PMCID: PMC3325044
Gerber JM, Qin L, Kowalski J, Smith BD, Griffin CA, Vala MS, Collector MI, Perkins B, Zahurak M, Matsui W, Gocke CD, Sharkis SJ, Levitsky HI, Jones RJ. Characterization of chronic myeloid leukemia stem cells. Am J Hematol. 2011 Jan;86(1):31-7. PMID: 21132730 or PMCID: PMC3010878
Ai J, Druhan LJ, Hunter MG, Loveland MJ, Avalos BR. LRG-Accelerated differentiation defines unique G-CSFR signaling pathways downstream of PU.1 and C/EBPε that modulate neutrophil activation. J Leuk Biol, 2008 May; 83(5); 1277-85. PMID: 18272588
Druhan LJ, Ai J, Massullo P, Kindwall-Keller T, Ranalli MA, and Avalos BR. Novel mechanism of G-CSF refractoriness in patients with severe congenital neutropenia. Blood. 2005 Jan 15;105(2):584-91. PMID: 15353486
Massullo P, Druhan LJ, Bunnell BA, Hunter MG, Robinson J, and Avalos BR. Aberrant Subcellular Targeting of the G185R Neutrophil Elastase Mutant Associated with Severe Congenital Neutropenia Induces Premature Apoptosis of Differentiating Promyelocytes. Plenary Paper, Blood. 2005 May 1;105(9):3397-404. PMID: 15657182
Hunter M, Avalos BR. Granulocyte colony-stimulating factors mutations in severe congenial neutropenia transforming to acute myelogenous leukemia confer resistance to apoptosis and enhance cell survival. Blood. 2000;95(6):2132-7. PMID: 10706885