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
Fun Fact: I biked across the country between my junior and senior year of high school
Email: waitman.aumann@emory.edu
Amanda MacGregor Harrington, MD
Education: BS, University of Georgia; MD, Medical College of Georgia
Fun Fact: I once won a Texas Hold’em poker tournament in college
Email: amanda.harrington@choa.org
Rafi Kazi, MD
Education: AB, Harvard University; MD, University of Arkansas
Fun Fact: I am fairly obsessed with my vegetable garden
Email: rafi.kazi@choa.org
Donald (“Rob”) Tope
Education: BS, Virginia Tech
Fun fact: I like long walks on the beach
Email: donald.tope@emory.edu
Dan Wechsler, MD, PhD
Education: AB, Harvard University; MD, CM, McGill University; PhD, McGill University
Fun Fact: I am a diehard Washington Nationals fan
Email: dan.wechsler@emory.edu
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
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. PubMed PMID: 25027513; PubMed Central 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;10(6):e0129776. PubMed PMID: 26075887; PubMed Central PMCID: PMC4467867.
Moreau K, Fleming A, Imarisio S, Lopez Ramirez A, Mercer JL, Jimenez-Sanchez M, Bento CF, Puri C, Zavodszky E, Siddiqi F, Lavau CP, Betton M, O'Kane CJ, Wechsler DS, Rubinsztein DC. PICALM modulates autophagy activity and tau accumulation. Nat Commun. 2014 Sep 22;5:4998. PubMed PMID: 25241929; PubMed Central PMCID: PMC4199285.
Heath JL, Weiss JM, Lavau CP, Wechsler DS. Effects of iron depletion on CALM-AF10 leukemias. Exp Hematol. 2014 Dec;42(12):1022-30.e1. PubMed PMID: 25193880; PubMed Central PMCID: PMC4261044.
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. PubMed PMID: 23487024; PubMed Central 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. PubMed PMID: 22952941; PubMed Central 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. PubMed PMID: 12461747.
Hyundai Hope on Wheels Young Investigator Award (2018-2020)