Overview
Leukemia is the most common cancer seen in childhood. Despite significant progress in the treatment of some pediatric leukemias, the prognosis for a subset of leukemias remains poor. Childhood leukemias that contain the CALM-AF10 fusion protein are especially hard to treat. The presence of CALM-AF10 leads to abnormally high levels of HOXA genes, which are involved in white blood cell development and are known to play a key role in leukemias. However, how CALM-AF10 expression results in elevated HOXA gene expression is unclear. We have previously shown that in order to activate HOXA genes, CALM-AF10 recruits another protein, CRM1, that normally functions to help move other proteins out of the cell nucleus. The involvement of CRM1 in the development of leukemias is novel and unexpected, and our lab is investigating the role of CRM1 in activating HOXA genes and causing leukemia. In particular, we are evaluating novel protein interactions with CRM1 as well as other (non-HOXA) targets of CALM-AF10.
Our current laboratory studies are focused on a novel role for CRM1 in pediatric leukemogenesis – our discovery that CRM1 is directly involved in HOXA gene activation has important implications for leukemias in which HOXA gene expression is increased (CALM-AF10, MLL-, NUP-fusions), and raises the possibility that a novel class of currently available CRM1 inhibitors (Selective Inhibitors of Nuclear Export – SINEs) may function by impairing processes other than just nuclear export. Finally, the investigation of non-HOXA CALM-AF10 target genes may allow for the development of novel approaches to treat these challenging leukemias. Through these approaches, we hope to identify novel therapeutic targets for difficult-to-treat childhood leukemias.
Waitman (“Wait”) Aumann, MD, MSc
Education: BS, University of Richmond; MSc, Georgetown University; MD, George Washington University
Email: waitman.aumann@emory.edu
Dan Wechsler, MD, PhD
Education: AB, Harvard University; MD, CM, McGill University; PhD, McGill University
Email: dan.wechsler@emory.edu
Dongdong (Julie) Chen, MS, Lioning Normal University
Lyndsey Alexander, BS, Kennesaw State University
Travis Reese, Emory University
Suhani Varma, Emory University
Amanda McGregor Harrington, MD (2018-2020), currently at University of Kentucky/Kentucky Children's Hospital
Rafi Kazi, MD (2018-2021), University of Rochester
Donald "Rob" Tope (2017-2021), Georgia Institute of Technology
Catherine Lavau, DVM, PhD (2006-2018), currently at Duke University
Sei-Gyung Sze, MD (2015-2017), currently at Maine Medical Center
Jacob Mercer, PhD (2011-2016), currently at Quintiles
Jessica Heath, MD (2010-2015), currently at the University of Vermont
Stephanie Fritch-Lilla, MD (2012-2014), currently at Children’s Hospital of Minnesota
Amanda Conway, PhD (2008-2013), currently at NIEHS
Jennifer Walker, MD (2008-2010), currently in Private Practice
Robert Greiner, MD (2007-2009), currently at Penn State Medical Center
Aumann WK, Heath JL, Conway AE, Sze SK, Gupta VK, Kazi RR, Tope DR, Wechsler DS, Lavau CP. Fusion of the CRM1 nuclear export receptor to AF10 causes leukemia and transcriptional activation of HOXA genes. Leukemia. 2021 Mar;35(3):876-880. doi: 10.1038/s41375-020-0998-3. Epub 2020 Jul 30. PMID: 32733011; PMCID: PMC7854800.
Lavau CP, Aumann WK, Sze SK, Gupta V, Ripple K, Port SA, Kehlenbach RH, Wechsler DS. The SQSTM1-NUP214 fusion protein interacts with Crm1, activates Hoxa and Meis1 genes, and drives leukemogenesis in mice. PLoS One. 2020 Apr 28;15(4):e0232036. doi: 10.1371/journal.pone.0232036. PMID: 32343715; PMCID: PMC7188244.
Conway AE, Haldeman JM, Wechsler DS, Lavau CP. A critical role for CRM1 in regulating HOXA gene transcription in CALM-AF10 leukemias. Leukemia. 2015 Feb;29(2):423-32. doi: 10.1038/leu.2014.221. Epub 2014 Jul 16. PMID: 25027513; PMCID: PMC4297268.
Mercer JL, Argus JP, Crabtree DM, Keenan MM, Wilks MQ, Chi JT, Bensinger SJ, Lavau CP, Wechsler DS. Modulation of PICALM Levels Perturbs Cellular Cholesterol Homeostasis. PLoS One. 2015 Jun 15;10(6):e0129776. doi: 10.1371/journal.pone.0129776. PMID: 26075887; PMCID: PMC4467867.
Conway AE, Scotland PB, Lavau CP, Wechsler DS. A CALM-derived nuclear export signal is essential for CALM-AF10-mediated leukemogenesis. Blood. 2013 Jun 6;121(23):4758-68. doi: 10.1182/blood-2012-06-435792. Epub 2013 Mar 13. PMID: 23487024; PMCID: PMC3674674.
Scotland PB, Heath JL, Conway AE, Porter NB, Armstrong MB, Walker JA, Klebig ML, Lavau CP, Wechsler DS. The PICALM protein plays a key role in iron homeostasis and cell proliferation. PLoS One. 2012;7(8):e44252. doi: 10.1371/journal.pone.0044252. Epub 2012 Aug 30. PMID: 22952941; PMCID: PMC3431333.
Wechsler DS, Engstrom LD, Alexander BM, Motto DG, Roulston D. A novel chromosomal inversion at 11q23 in infant acute myeloid leukemia fuses MLL to CALM, a gene that encodes a clathrin assembly protein. Genes Chromosomes Cancer. 2003 Jan;36(1):26-36. doi: 10.1002/gcc.10136. PMID: 12461747.
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