Department of microbiology and molecular genetics

Faculty profile

• MD - Loma Linda University 1975
• Internal medicine residency - University of Alabama at Birmingham, 1975-1978
• Hematology-oncology fellow - University of Alabama at Birmingham, 1978-1981
• Assistant professor - University of Alabama at Birmingham, 1982-1988
• Associate professor of medicine - University of Washington, 1989-1998
• Director of the Center for Molecular Biology & Gene Therapy - Loma Linda University, 1999
• Current research interests
• Recent publications
• Teaching

Current research interests

My laboratory is investigating the mechanisms through which hematopoietic growth factors, particularly granulocyte-macrophage colony-stimulating factor (GM-CSF), regulate the proliferation and differentiation of normal and malignant myeloid cells. Normal hematopoietic progenitor cells require peptide growth factors (cytokines) for proliferation and survival. Identification of the several signal transduction steps through which cytokines variably induce cells to proliferate, or alternately to terminally differentiate, is of fundamental importance to understanding the processes involved in leukemic transformation. Our studies encompass a spectrum of projects, ranging from basic investigations to clinical trials.

Basic science studies

We have performed extensive structure-function studies of the human GM-CSF receptor through use of mutagenesis and gene transfer studies. We have particularly focused on the a chain of the receptor complex, though reports on the § chain have been published as well. We have demonstrated that the short intracytoplasmic domain of the a chain is required for both proliferation and differentiation signals. Indeed there appear to be at least two domains of the a chain which activate different signaling events. A proximal domain activates an as-yet unidentified tyrosine kinase and supports proliferation and expression of F4/80.A distal domain is required for activation of the Jak2 tyrosine kinase, and regulates expression of CD80, CD86, and other dendritic cell markers.

Our mapping studies have identified that expression of the pim-1 kinase is a key event in the generation of proliferative signals through the GM-CSF receptor, and have led us to extensively study the biology and biochemistry of the pim-1 gene product. Our studies have thus far demonstrated that, unlike most cytoplasmic serine kinases, expression of pim-1is highly regulated by hematopoietic cytokines such as GM-CSF. Pim-1 kinase acts as a survival factor, inhibiting apoptosis in hematopoietic cells deprived of cytokines. In part this anti-apoptotic effect is mediated through regulation of a downstream death inhibitor, bcl-2. However, not all of the effects of the Pim-1 protein can be explained by induction of bcl-2 expression, and evidence suggests that Pim-1 kinase may directly or indirectly regulate other members of the bcl-2 family. Currently we are looking at signal transduction pathways through which pim-1 might regulate expression of bcl-2.

Translational studies

Because of its role as a survival protein we feel that may be an attractive target for intervention through pharmacologic or gene manipulation methods. We have developed dominant negative variants of Pim-1 protein which markedly enhance cell death and which sensitize hematopoietic cells to the effects of chemotherapy drugs. We are developing methods to evaluate these proteins in actual clinical leukemia samples. An attractive method may involve construction of cell-permeable proteins by engineering ãvectoroe domains onto the recombinant protein molecule, conferring the ability to enter most cells. We have identified several such vector sequences and are exploring their use in developing novel pharmaceutical agents for manipulation of signal transduction processes.

Clinical studies

We are already using the GM-CSF receptor as a target for experimental therapeutics. We have a phase I study of a diphtheria toxin/GM-CSF chimeric protein ongoing, for treatment of relapsed or refractory acute myelogenous leukemia in adults.

Lilly Laboratory

Michael B. Lilly, MD, principal investigator
Marina Zemzkova, PhD, research associate
Chris Corsentino, research assistant
Bin Yan, MD, PhD, graduate student

Dr. Lilly's laboratory is located on the first floor of Mortensen Hall, in the Center for Molecular Biology and Gene Therapy.

Recent publications

Click on the symbol beside the reference to read the corresponding abstract.

Lilly M, Frankel A, Salo J, Kraft AS:Ê The variable carboxy-terminal domain of the GM-CSF receptor a chain regulates activation and autophosphorylation of the Jak2 kinase.Ê (Submitted,Ê1999).

Lilly M, Kiskonen P, Sandholm J, Cooper JJ, Kraft AS. 1999. The Pim-1 kinase prevents apoptosis-associated mitochondrial dysfunction, and supports cytokine-independent survival of myeloid cells in part through regulation of bcl-2 expression.Ê Oncogene 18:4022-4031.

Frankel A, Lilly M, Kreitman R, Hogge D, Beran M, Freedman MH, Emanuel PD, McLain C, Hall P, Tagge E, Berger M, Eaves C. 1998. Diptheria toxin fused to granulocyte-macrophage colony-stimulating factor is toxic to blasts from patients with juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia.Ê Blood 92:4279-4286.

Matsuguchi T, Lilly MB, Kraft AS. 1998. Cytoplasmic domains of the human granulocyte-macrophage colony-stimulating factor receptor § chain (h-§-c) responsible for human GM-CSF-induced myeloid cell differentiation. J Biol Chem 273:19411-19418.

Lilly M, Kraft A. 1997. Enforced expression of the 33kd pim-1 kinase enhances factor-independent growth and inhibits apoptosis in murine myeloid cells.Ê Cancer Res 57:5348-5355.

Matsuguchi T, Zhao Y, Lilly MB, Kraft AS. 1997. The cytoplasmic domain of the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor a subunit is essential for both GM-CSF-mediated growth and differentiation.Ê J Biol Chem 272:17450-17459.

Lilly M, Vo K, Lee T, Takahashi G. 1996. Bryostatin 1 acts synergistically with interleukin 1 to promote the release of G-CSF and other myeloid cytokines from marrow stromal cells.Ê Exp Hematol 24:613-621.

Sensebe L, Li J, Lilly M, Crittenden C, Herve P, Charbord P, Singer J. 1995. Non-transformed colony-derived stromal cell lines from normal human marrows.Ê I.Ê Growth requirements, characterization ,and myelopoieisis-supportive ability.Ê Exp Hematol 23:507-513.

Polostkya A, Zhao C, Lilly M, Kraft A. 1994. Mapping the intracytoplasmic regions of the a granulocyte-macrophage colony-stimulating factor receptor necessary for cell growth regulation.Ê J Biol Chem 269:14607-14613.

Polostkya A, Zhao C, Lilly M, Kraft A. 1993. A critical role for the intracellular domain of the a chain of the GM-CSF receptor in cell cycle transition.Ê Cell Growth & Diff 4:525-531.

Lilly M, Le T, Holland P, Hendrickson S. 1992. Expression of the pim-1 kinase is specifically induced in myeloid cells by growth factors whose receptors are structurally related.Ê Oncogene 7:727-732.

Teaching

• [Faculty/research]

School of Medicine - Graduate School - Loma Linda University

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