Waldenström's macroglobulinemia pathophysiology

Jump to navigation Jump to search

Waldenström's macroglobulinemia Microchapters

Home

Patient Information

Overview

Historical Perspective

Classification

Pathophysiology

Causes

Differentiating Waldenström's macroglobulinemia from other Diseases

Epidemiology and Demographics

Risk Factors

Screening

Natural History, Complications and Prognosis

Diagnosis

Diagnostic Study of Choice

History and Symptoms

Physical Examination

Laboratory Findings

Electrocardiogram

Bone Marrow Aspiration and Biopsy

Electrophoresis and Immunofixation

Chest X Ray

CT

MRI

Echocardiography or Ultrasound

Other Imaging Findings

Other Diagnostic Studies

Treatment

Medical Therapy

Surgery

Primary Prevention

Secondary Prevention

Cost-Effectiveness of Therapy

Future or Investigational Therapies

Case Studies

Case #1

Waldenström's macroglobulinemia pathophysiology On the Web

Most recent articles

Most cited articles

Review articles

CME Programs

Powerpoint slides

Images

American Roentgen Ray Society Images of Waldenström's macroglobulinemia pathophysiology

All Images
X-rays
Echo & Ultrasound
CT Images
MRI

Ongoing Trials at Clinical Trials.gov

US National Guidelines Clearinghouse

NICE Guidance

FDA on Waldenström's macroglobulinemia pathophysiology

CDC on Waldenström's macroglobulinemia pathophysiology

Waldenström's macroglobulinemia pathophysiology in the news

Blogs on Waldenström's macroglobulinemia pathophysiology

Directions to Hospitals Treating Waldenström's macroglobulinemia

Risk calculators and risk factors for Waldenström's macroglobulinemia pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Mirdula Sharma, MBBS [2]

Overview

Waldenström macroglobulinemia is an uncontrolled clonal proliferation of terminally differentiated B lymphocytes, which are normally involved in humoral immunity.[1] Genes involved in the pathogenesis of waldenström macroglobulinemia include MYD88-L265P, and CXCR4. The progression to waldenström macroglobulinemia usually involves the MYD88/IRAK, and PI3K/Akt/mTOR molecular pathways. [2]

Pathogenesis

  • Waldenström Macroglobulinemia is uncontrolled clonal proliferation of terminally differentiated B lymphocytes, which are normally involved in humoral immunity.[1]
  • In Waldenström Macroglobulinemia, peripheral B lymphocyte are stimulated to undergo somatic hypermutation of the immunoglobulin heavy chain gene in the germinal center, without class switching.

Molecular pathway alteration

  • MYD88/IRAK:
  • MYD88/IRAK pathway has an important role in pathogenesis of Waldenström Macroglobulinemia.[3]
  • The toll-like receptor and interleukin-1 receptor signaling recruits Interleukin-1 receptor associated kinase 4 to the receptor causing activation of transcription factors of the NF-kB family.
  • Bruton tyrosine kinase (BTK) phosphorylation in Waldenström Macroglobulinemia cells helps in B cell over growth and survival.
  • PI3K/Akt/mTOR
  • Normally, PI3K/Akt/mTOR pathway signals to inhibit apoptosis.
  • In Waldenström Macroglobulinemia, activating mutation of PI3K/Akt/mTOR pathway serves toward growth and proliferation of tumor cells.
  • In Waldenström Macroglobulinemia, various other factors effect PI3K/Akt/mTOR pathway signaling, as follow:
  • Activators:
  • MYD88 L265P mutation
  • Bone marrow microenvironment - through cytokines such as insulin-like growth factor (IGF- 1) or stromal- derived factor (SDF-1)
  • PTEN - a negative regulator of PI3K/Akt/mTOR pathway is decreased which causes unopposed activation of PI3K/Akt/mTOR pathway in Waldenström Macroglobulinemia.
  • Inhibitor:
  • Akt - inhibited by perifosine
  • mTOR - inhibited by RAD001

Genetics

  • Development of Waldenström Macroglobulinemia is the result of multiple gene mutations.[2]
  • Genes involved in pathogenesis of Waldenström Macroglobulinemia are:
  • MYD88-L265P in chromosome 3p22.2
  • MYD88: activating point mutation of MYD88 augments growth and survival of both normal and neoplastic B cells by preventing apoptosis. Point mutation of MYD88 leads to leucine (L) to proline (P) substitution in codon 265 (L265P) of MYD88 and produces constantly overactive protein causing proliferation of malignant cells that should normally undergo apoptosis.[2][4]
  • Monoclonal gammopathy of undetermined significance patients found to have MYD88 L265P mutation are associated with a significantly higher risk of progression to Waldenström Macroglobulinemia or to other lymphoproliferative disorders.[3]
  • CXCR4
  • Patients with Waldenström Macroglobulinemia with co-existing mutation of MYD88 & CXCR4 are more likely to have hyperviscosity syndrome and bone marrow involvement.[2]
  • Waldenström Macroglobulinemia is associated with following chromosome abnormalities:[2]
  • Deletions of 6q23 and 13q14
  • Gains of 3q13-q28, 6p and 18q

Epigenetics

  • Three most common epigenetic causes are DNA methylation, histone acetylation, and non-coding RNAs such as miRNAs.[3]
  • Upregulation of miRNAs 155, 184, 206, 363, 494, and 542-3p occurs in Waldenström Macroglobulinemia; among which miRNA-155 has a crucial role in tumor cell growth and proliferation in Waldenström Macroglobulinemia.
  • Gene transcription through histone acetylation occurs following increased expression of miRNA-206 and reduced expression of miRNA-9.

Associated Conditions

Several studies showed an increased incidence of second cancers in patients with Waldenström macroglobulinemia as follows:[5]

Microscopic Pathology

Following are the images of microscopic histology of Waldenström's macroglobulinemia:

Immunohistochemistry

Malignant cells in Waldenström Macroglobulinemia:[2]

  • Express Pan B-cell antigens (CD19, CD20, CD22, CD79A), and CD5
  • Variable expression of CD11c, CD43, CD25
  • Most express IgM surface immunoglobulin, while fewer express IgG or IgA and lack IgD

References

  1. 1.0 1.1 Waldenström's macroglobulinemia. Wikipedia (2015)https://en.wikipedia.org/wiki/Waldenström%27s_macroglobulinemia#Pathophysiology Accessed on November 6, 2015
  2. 2.0 2.1 2.2 2.3 2.4 2.5 Ngo VN, Young RM, Schmitz R, Jhavar S, Xiao W, Lim KH, Kohlhammer H, Xu W, Yang Y, Zhao H, Shaffer AL, Romesser P, Wright G, Powell J, Rosenwald A, Muller-Hermelink HK, Ott G, Gascoyne RD, Connors JM, Rimsza LM, Campo E, Jaffe ES, Delabie J, Smeland EB, Fisher RI, Braziel RM, Tubbs RR, Cook JR, Weisenburger DD, Chan WC, Staudt LM (2011). "Oncogenically active MYD88 mutations in human lymphoma". Nature. 470 (7332): 115–9. doi:10.1038/nature09671. PMID 21179087.
  3. 3.0 3.1 3.2 Waldenström macroglobulinemia. International Waldenström Macroglobulinemia foundation (2015)http://www.iwmf.com/sites/default/files/docs/WM_Review_Ghobrial_Jan2014.pdf Accessed on November 12, 2015
  4. Waldenström macroglobulinemia. Genetics Home Reference (2015)http://ghr.nlm.nih.gov/condition/waldenstrom-macroglobulinemia Accessed on November 9, 2015
  5. Morra E, Varettoni M, Tedeschi A, Arcaini L, Ricci F, Pascutto C, Rattotti S, Vismara E, Paris L, Cazzola M (2013). "Associated cancers in Waldenström macroglobulinemia: clues for common genetic predisposition". Clin Lymphoma Myeloma Leuk. 13 (6): 700–3. doi:10.1016/j.clml.2013.05.008. PMID 24070824.
  6. Chi PJ, Pei SN, Huang TL, Huang SC, Ng HY, Lee CT (2014). "Renal MALT lymphoma associated with Waldenström macroglobulinemia". J. Formos. Med. Assoc. 113 (4): 255–7. doi:10.1016/j.jfma.2011.02.007. PMID 24685302.

Template:WH Template:WS