John Crispino, PhD

John Crispino, PhD

Associate Professor of Medicine, Feinberg School of Medicine
Associate Director of Education, Robert H Lurie Comprehensive Cancer Center

j-crispino@northwestern.edu

Northwestern University
Division of Hematology/Oncology
303 East Superior Street
Lurie 5-113
Chicago, IL 60611
Phone: (312) 503-1504

Research Description:

Research in the Crispino lab is focused on investigating theregulatory mechanisms governing normal and malignant blood cell development,with an emphasis on understanding the growth of erythroid cells (red bloodcells) and megakaryocytes (platelet-producing cells). In addition, we aregreatly interested in learning how changes in normal essential regulatorymolecules lead to human blood diseases, including leukemias, myelodysplasticsyndromes (MDS) and myeloproliferative neoplasms (MPNs). Areas of majorinterest include:

Mechanisms of leukemogenesis in children with Down syndrome

Several years ago, we discovered that the zinc fingertranscription factor GATA-1 is mutated in Acute Megakaryoblastic Leukemia(AMKL) in children with Down syndrome (DS). We further found that GATA1 mutations are also present in apre-leukemia, named transient myeloproliferative disorder, which is relativelycommon in infants with Down syndrome. Current studies in the lab are focused oncharacterizing the role of GATA-1 in normal megakaryocyte development and oninvestigating how GATA1 mutationscontribute to leukemia. In related experiments, we are also studying the mechanismsby which trisomy 21 promotes the development of leukemia. Our long-term goal isto unravel the mystery of why children with DS are predisposed to leukemia.These studies are performed in collaboration with physicians at Children’sMemorial Hospital and the Children’s Oncology Group. In addition to studyingmouse models of Down syndrome, we are now harnessing the power of inducedpluripotent stem (iPS) cells to define the role of trisomy 21 in leukemia. Incollaboration with Drs. Vasil Galat and Marcelo (Bento) Soares at Children’sMemorial Research Center, we are comparing gene expression and methylationprofiles of iPS cells derived from euploid and trisomic human cells.

Regulationof megakaryocyte proliferation, polyploidization and terminal maturation:

Megakaryocytes, the precursors to platelets, are one of thefew cells types to undergo polyploidization in the normal course of maturation.We are using high throughput methods to identify genes that control the switchbetween the proliferative and the endomitotic cell cycle, such as survivin. Inaddition, we are examining the contribution of key transcription factors, suchas GATA-1, GATA-2 and Ets proteins in the regulation of megakaryocyte geneexpression, terminal differentiation and lineage commitment.

Developmentof novel therapeutics for human megakaryocytic neoplasms:

In an ongoing collaboration with the Broad Institute, wehave identified a set of small molecules that rapidly and robustly induceproliferation arrest and terminal maturation of malignant megakaryocytes,including those that harbor mutations in GATA1,JAK3, or c-MPL, as well as thosethat express the t(1;22) fusion protein associated with pediatric non-DS AMKL.These small molecules induce features of megakaryocyte differentiation,including extensive polyploidization and expression of markers of terminaldifferentiation, but they do not appear to promote platelet release. We arecurrently developing these compounds as potential new therapies for blooddisorders, including acute megakaryocytic leukemia and primarymyelofibrosis.

Control ofred blood cells development:

Survivin, a member of the inhibitor of apoptosis (IAP)family that also plays an essential role in cytokinesis, is differentiallyexpressed during erythroid versus megakaryocyte development. We recentlyreported that survivin is required for the maintenance of hematopoietic stemand progenitor cells as well as for red blood cell development. More recently,we have found that survivin is highly expressed in post-mitotic erythroblasts.We are currently studying the contribution of survivin to terminal maturationof erythroid cells, including enucleation.

Lab Members:

Niket Bubna, Masters in Biotechnology student
Tim Chlon, IGP student

Lou Dore, IGP student

Zan Huang, Post-doctoral fellow

Ganesan Keerthivasan, Research Associate

Sebastien Malinge, Post-doctoral fellow

Monika Stankiewicz, Post-doctoral fellow

Jeremy Wen, Research Associate

Publications (2005-present):

Crispino, JD. (2005) GATA1mutations in Down syndrome: implications for biology and diagnosis of childrenwith transient myeloproliferative disorder and acute megakaryoblastic leukemia.Pediatric Blood and Cancer,44:40-44.

Crispino, JD. (2005) GATA-1 in normal and malignanthematopoiesis, Seminars in Cell andDevelopmental Biology 16:137-147.

Muntean, A and Crispino, JD. (2005) Differentialrequirements for the activation domain and FOG-interaction surface of GATA-1 inmegakaryocyte gene expression and development, Blood 106:1223-1231.

Gurbuxani,S, Xu, Y, Keethivasan, G Wickrema, A and Crispino,JD (2005) Differential requirements for survivin in hematopoietic celldevelopment. PNAS 102:11480-11485.

Crispino, JD. (2006) Up and Down in Downsyndrome: AMKL. Blood 107:1251-1252.

Mundschau,G and Crispino J. (2006) GATA1s goesgermline. Nature Genetics,38:741-742.

Xu, Y,Leung, CG, Lee, DC, Kennedy, BK, and Crispino,JD. (2006) MTB, the murine homologue of condensin II subunit CAP-G2represses transcription and promotes erythroid cell differentiation. Leukemia, 20:1261-1269.

Muntean,A, Ge, Y, Taub, JW and Crispino, JD. (2006)Transcription Factor GATA-1 and Down syndrome Leukemogenesis. Leukemia and Lymphoma 47: 986-997.

Walters,DK, Mercher, T, Goss, V, O’Hare, T, Tyner, JW, Loriaux, M, Gu, T-L, Lee, K,Eide, CA, Wong, MJ, Stoffregen, EP, McGreevey, L, Moore, SA, Crispino, J, Boggon, T, Heinrich, MC,Deininger, MW, Polakiewicz, RD, Gilliland, G, and Druker, BJ. (2006) Novelactivating alleles of JAK3 in acute megakaryoblastic leukemia. Cancer Cell 10:65-75.

Vyas, P,and Crispino, JD. (2007) MolecularInsights into Down syndrome associated leukemia. Curr. Op Pediatrics 19:9-14.

Crispino, JD. (2007) On the origins ofmegakaryocytes. Blood 109:1340-1341.

Muntean,AG, Pang, L, Poncz, M, Dowdy, S, Blobel, G, and Crispino, JD. (2007) Cyclin D-Cdk4 is regulated by GATA-1 andrequired for megakaryocyte growth and polyploidization. Blood 109:5199-5207.

Joslin, J,Fernald, AA, Tennant, TR, Davis, EM, Kogan, SC, Anastasi, J, Crispino, JD and Le Beau, MM. (2007)Loss of EGR1, a candidate gene in thedel(5q), leads to the development myeloid neoplasms. Blood 110:719-726.

Leung, CG,Xu, Y, Mularski, B, Liu, H, Gurbuxani, S, and Crispino, JD. (2007) Requirements for Survivin in terminaldifferentiation of erythroid cells and maintenance of hematopoietic stem andprogenitor cells. Journal of ExperimentalMedicine 204:1603-1611.

Norton, A,Fisher, C, Liu, H, Wen, Q, Mundschau, G, Fuster, JL, Hasle, H, Zeller, B, Webb,D, O’Marcaigh, A, Sorrell, A, Hilden, J, Gamis, A, Crispino, JD and Vyas, P. (2007) Frequency of JAK3, JAK2, and c-MPLmutations in TMD and AMKL blasts in children with Down syndrome. Blood 110:1078-1079.

Wickrema,A and Crispino, JD. (2007) Erythroidand Megakaryocytic Transformation. Oncogene,26:6803-6815.

Huang, Z,Richmond, TD, Muntean, A, Barber, DL, Weiss, MJ, and Crispino, JD. (2007) STAT1 promotes megakaryopoiesis downstream ofGATA-1. Journal of Clinical Investigation117:3890-3899.

Kirsammer,G, Jilani, S, Liu, H, Davis, E, Gurbuxani, S, Le Beau, MM, and Crispino, JD. (2008) Highly penetrantmyeloproliferative disease in the Ts65Dn mouse model of Down syndrome. Blood, 111:767-775.

Kang JA, Zhou Y, Weis TL, LiuH, Ulaszek J, Satgurunathan N, Zhou L, van Besien K, Crispino J, Verma A, Low PS, Wickrema A. (2008) Osteopontinregulates actin cytoskeleton and contributes to cell proliferation in primaryerythroblasts. Journal of BiologicalChemistry 283:6997-7006.

McCrann,DJ, Yezefski T, Nguyen HG, Liu H, Wen Q, CrispinoJD, and Ravid K. (2008) Survivin overexpression in transgenic mice alonedoes not alter megakaryocyte ploidy nor interfere with erythroid/megakaryocyticlineage development. Blood 101:4092-4095.

Malinge,S, Izraeli, S, and Crispino JD.(2009) Insights into the manifestations, outcomes and mechanisms ofleukemogenesis in Down syndrome. Blood113:2619-2628.

Stankiewicz,MJ, and Crispino JD. (2009) ETS2 andERG promote megakaryopoiesis and synergize with loss of GATA-1 to immortalizehematopoietic progenitor cells. Blood113:3337-3347.

Wen, Q,Leung, C, Huang, Z, Small, S, Reddi, AL, Licht, JD and Crispino JD. (2009) Survivin is not required for the endomitoticcell cycle of megakaryocytes. Blood 114:153-156.

Abdel-Wahab,O., Mullally, A, Hedvat, C, Garcia-Maero, G, Patel, J, Malinge S, Yao, J,Kilipavaara, O, Wadleigh, M, Bhat, R, Huberman, K, Thomas, S, Dolgalev, I,Heguy, A, Paietta, E, Le Beau, M, Beran, M, Tallman, M, Kantarjian, H, Ebert,B, Gilliland, DG, Crispino, JD, andLevine, R. (2009) Genetic characteristics of TET1, TET2, and TET3 alterations in myeloidmalignancies. Blood 114:144-147.

Chou, St,Khandros, E, Bailey, C, Nichols, KE, Vakoc, C, Yao, Y, Huang, Z, Crispino, JD, Blobel, GA, and Weiss,MJ. Graded repression of PU1/Sfpi1 gene transcription by GATA factors regulateshematopoietic cell fate. Blood, inpress. Pre-published on line June2, 2009. DOI 10.1182/blood-2009-03-207944.

Bhat, R,Malinge, S, Gamis, AS, Sorrell, AD, Hilden, JM, Paietta, E, Tallman, MS,Ketterling, RP, and Crispino, JD.Mutational analysis of candidate tumor associated genes in acutemegakaryoblastic leukemia. Leukemia, inpress.

Huang, Z,Dore, LC, Li, Z, Orkin, SH, Feng, G, Lin, S, and Crispino JD. GATA2 reinforces megakaryocyte development in theabsence of GATA-1. MCB, in press.