Warts in Children

Duojia (DJ) Pan – Department of Molecular Biology & Genetics

Warts in Children | Johns Hopkins Medicine

Adjunct Professor

The control of organ size is a long-standing puzzle in developmental biology. My laboratory uses Drosophila and mice as model systems to investigate size-control mechanisms in normal development and their pathological roles in cancer. Our general approach is to use Drosophila as a genetic tool to discover size-control genes.

We then use a combination of genetics and biochemistry to place these genes into signaling networks. Finally, we use mouse genetics to investigate how the size-control mechanisms we have uncovered in Drosophila regulate tissue homeostasis in mammals.

With these concerted efforts, we aim to decipher the general mechanisms underlying control of organ size in animals.

To discover size-control genes, we conducted genetic screens in Drosophila for mutations that result in overgrowth of adult structures. These overgrowth mutants can be broadly divided into two classes: those associated with an increase in cell size and those associated with an increase in cell number.

Earlier studies from my laboratory focused on the cell-size mutants, which led to the discovery of a cell size-controlling pathway that involves the tuberous sclerosis tumor suppressors Tsc1 and Tsc2, the small GTPase Rheb, and the protein kinase TOR.

The functional link between Tsc1 and Tsc2 and TOR uncovered in Drosophila paved the way for the clinical development of mTOR inhibitor everolimus in the treatment of subependymal giant cell astrocytoma associated with tuberous sclerosis.

Much of our recent work focused on the overgrowth mutants associated with an increase in cell number. These studies led us to elucidate the Hippo signaling pathway, which plays a critical role in stopping organ growth by simultaneously promoting cell death and cell cycle exit as cells enter the differentiation phase of organogenesis.

In Drosophila, the Ste20- kinase Hippo (Hpo) phosphorylates and activates the NDR family kinase Warts (Wts). Wts, in turn, phosphorylates and inactivates the oncoprotein Yorkie (Yki) by excluding it from the nucleus, where it normally functions as a coactivator for the DNA-binding transcription factor Scalloped (Sd).

Building on insights from Drosophila, we further delineated a mammalian Hippo pathway that links the mammalian homologues of Hpo (Mst1/2), Wts (Lats1/2), Yki (YAP), and Sd (TEAD/TEF family members) in an analogous signaling cascade.

Using a conditional YAP transgenic mouse model, we showed that the mammalian Hippo pathway is a potent regulator of organ size and that its dysregulation leads to tumorigenesis in mammals.

Our current and future research directions include: 1) elucidating the composition, mechanism and regulation of Hippo signaling using Drosophila as a model; 2) understanding the role of Hippo signaling in mammalian development, regeneration and tumorigenesis using mouse genetics; 3) investigating the ancestral role of Hippo signaling in unicellular organisms; 4) developing small-molecule modulators of the Hippo pathway for cancer and regenerative medicine.

Source: https://mbg.jhmi.edu/people/duojia-dj-pan/

WHIM Syndrome – NORD (National Organization for Rare Disorders)

Warts in Children | Johns Hopkins Medicine

McDermott DH. Warts Hypogammaglobulinemia, Infections, and Myelokathexis Syndrome in Steihm’s Immune Deficiencies. 2014;709-717.

Heusinkveld LE, Majumdar S, Gao JL, et al. WHIM Syndrome: from Pathogenesis Towards Personalized Medicine and Cure. J Clin Immunol. 2019; 39(6):532-556. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698215/

McDermott DH, Pastrana DV, Calvo KR, et al. Plerixafor for the Treatment of WHIM Syndrome. N Engl J Med. 2019; 380(2): 163-170. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425947/

McDermott DH, Qiu L, Velez D, et al. A phase 1 clinical trial of long-term, low-dose treatment of WHIM syndrome with the CXCR4 antagonist plerixafor. Blood 2014;123: 2308-16.

Badolato R, Dotta L, Tassone L, et al. Tetralogy of Fallot is an uncommon manifestation of Warts, Hypogammaglobulinemia, Infections, and Myelokathexis syndrome. J Pediatr. 2012;161:763-765. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3458406/

Beaussant Cohen S, Fenneteau O, Plouvier E, et al. Description and outcome of a cohort of 8 patients with WHIM syndrome from the French Severe Neutropenia Registry. Orphanet J Rare Dis. 2012;7:71. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3585856/

McDermott DH, Liu Q, Ulrick J, et al. The CXCR4 antagonist plerixafor corrects panleukopenia in patients with WHIM syndrome. Blood 2011;118:4957-4962. http://www.ncbi.nlm.nih.gov/pubmed/21890643

Diaz GA. Released on a WHIM. Blood 2011;118:4764-4765. http://www.ncbi.nlm.nih.gov/pubmed/22053172

Donadieu J, Fenneteau O, Beaupain B, Mahlaoui N, Chantelot CB. Congenital neutropenia: diagnosis, molecular bases and patient management. Orphanet J Rare Dis. 2011;6:26. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3127744/

McDermott DH, Lopez J, Deng F, et al. AMD3100 is a potent antagonist at CXCR4R334X, a hyperfunctional mutant chemokine receptor and cause of WHIM syndrome. J Cell Mol Med. 2011;15:2071-2081. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3071896/

Dale DC, Bolyard AA, Kelley ML, et al. The CXCR4 antagonist plerixafor is a potential therapy for myelokathexis, WHIM syndrome. Blood 2011;118:4963-4966. http://www.ncbi.nlm.nih.gov/pubmed/21835955

Kawai T, Malech HL. WHIM syndrome: congenital immune deficiency disease. Curr Opin Hematol. 2009;16:20-26. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2673024/

Hagan JB, Nguyen PL. WHIM syndrome. Mayo Clin Proc. 2007;82:1031. http://www.ncbi.nlm.nih.gov/pubmed/17803866

Taniuchi S, Masuda M, Fujii Y, et al. The role of a mutation of the CXCR4 gene in WHIM syndrome. Haematologica. 2005;90:1271-1272. http://www.ncbi.nlm.nih.gov/pubmed/16154852

Gorlin RJ, Gelb B, Dian GA, et al. WHIM syndrome, an autosomal dominant disorder: clinical, hematological, and molecular studies. Am J Med Genet. 2000;91:368-376. http://www.ncbi.nlm.nih.gov/pubmed/10767001

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:193670; Last Update: 02/06/2019. Available at: http://omim.org/entry/193670 Accessed Jan 27, 2020.

Diaz G, Gulino V. WHIM Syndrome (Warts, Hypogammaglobulinemia Infections Myelokathexis). Orphanet Encyclopedia, June 2004. Available at: https://www.orpha.net/data/patho/GB/uk-Whim.pdf Accessed Jan 27, 2020.

Source: https://rarediseases.org/rare-diseases/whim-syndrome/