Mast cell mutations: JAK2 and myeloproliferative neoplasms
- JAK2 is a helper protein that helps other molecules send signals to make more cells and to increase inflammation.
- JAK2 mutation V617F makes some cells more responsive to growth factors, so they grow too much. These cells include red blood cells, platelets and mast cells.
- Marker associated with other myeloproliferative diseases essential thrombocythemia (too many platelets), polycythemia vera (too many red blood cells), myelofibrosis (fibrosis of bone marrow).
- About 5% of SM patients have JAK2 V617F mutation. Indicates higher probability of developing another myeloproliferative disease.
- Doesn’t necessary mean lifespan is shorter.
Heritable mutations in mastocytosis
- About 75% of MCAD patients have at least one first degree relative with MCAD.
- The CKIT D816V mutation is not known to be heritable, but other CKIT mutations have been found in multiple family members.
Progression of mast cell diseases (Part 1)
- Life expectancy with indolent systemic mastocytosis (ISM) is normal.
- Average age at diagnosis of ISM is 49.
- Type and severity of symptoms vary and do not correlate with disease type, presence of CKIT D816V mutation or tryptase level.
- Mediator related symptoms are not indicative of aggressive or progressing disease.
- Organ swelling is not always indicative of ASM. Organs can be swollen for many years without functional damage or C findings.
Progression of mast cell diseases (Part 2)
- 5-10 years from diagnosis with ISM, 1.7% of patients progressed to SSM/ASM.
- 20-25 years from diagnosis with ISM, 8.5% of patients progressed to SSM/ASM.
- Risk of transformation of ISM to acute leukemia or ASM was less than 1% and 3% respectively.
- ASM and MCL are associated with accumulation of neoplastic mast cells in organs, impairment of organ function, drug resistance, poor prognosis and organ failure.
- In most SSM patients, disease stays stable over years or decades.
- SSM patients have higher incidence of anemia, constitutional symptoms and mast cell mediator levels than ISM patients.
- SSM is diagnosed later than ISM, around 64 years.
- ASM can be slow progressing and stable for many years or rapidly progressing.
- During progression of ASM and MCL, some patients lose the CKIT D816V mutation.
- Slow progression ASM can be kept under control for several months or even years with interferon and cladribine.
- In a group of 342 patients, 0.6% ISM patients developed MCL or AML, 6.5% ASM, and 13% SM-AHNMD.
- It is possible for disease to convert to less severe category.
Progression of mast cell diseases (Part 3)
- Mast cell accumulation is mostly due to decrease in apoptosis (cell death) rather than excessive proliferation.
- 20-30% of SM patients have tryptase below 20 ng/ml.
- If you test negative for CKIT D816V in blood, you may still be positive.
- Bone marrow test for CKIT D816V is most accurate.
- Histamine intolerance has been proposed as deficiency of enzymes to metabolize histamine. There is no evidence that this occurs in mast cell disease.
- 33% of MCAS patients are positive for elevated tryptase, 56% n-methylhistamine, 44% PGD2.
- 66% of patients with MCAS have major or complete regression in symptoms after one year of treatment.
Progression of mast cell diseases (Part 4)
- ISM is not life threatening in and of itself. Anaphylaxis, a symptom of ISM, is life threatening.
- 49% of SM patients experience anaphylaxis in their lifetime. 48% of anaphylaxis episodes in ISM patients were severe.
- There is no consensus on what is a normal count of mast cells in GI tract. Some healthy patients have more than 20 mast cells/hpf.
- Most patients with adult onset cutaneous mastocytosis also have systemic mastocytosis.
- Early studies indicated CM and MCAD were different, but frequency of CKIT mutations the same in patients with CM, SM and MCAS (about 86% in each group in one study). NOTE: The CKIT mutations were not always the D816V mutation.
- Patients with MMAS (monoclonal mast cell activation syndrome) and MCAS (mast cell activation syndrome) never have CM.
- ASM and MCL patients frequently lack CM.
Progression of mast cell diseases (Part 5)
- 55% of pediatric mastocytosis cases occur in the first two years of life.
- 35% occur between ages of 15 and 18.
- Cutaneous mastocytosis can result in mediator release symptoms without having systemic mastocytosis.
- 2/3 of childhood mastocytosis patients had complete resolution of cutaneous disease and symptoms before adulthood. They were not treated with steroids, PUVA or chemo drugs.
- Bone marrow biopsies of children with CM often show more mast cells than normal. High bone marrow mast cells in these children does not affect resolution.
- In a study of 50 pediatric CM patients, 86% had a CKIT mutation and36% had the D816V mutation.
Mast cell mutations: TET2 and mutation profiles of aggressive subtypes
- TET2 is mutated in 20.8-29% of SM patients.
- Several mutations are seen.
- TET2 is involved in DNA methylation which affects gene expression.
- 96% of SM patients with major blood abnormalities had mutations in at least two genes regardless of SM subtype.
Mast cell mutations: SRSF2 in SM-AHNMD
- SRSF2 is a protein that affects gene expression.
- An SRSF2 mutation was found in 24-37% of SM patients.
- Most common mutation in SM after CKIT D816V.
- Strongly associated with SM-AHNMD.
- Also found in other cell types besides mast cells. In SM-AHNMD, may cause both mast cell disease and associated blood disorder.
Anticholinergic use and dementia
- People who took higher amounts of anticholinergics had an increased risk of dementia.
- Some medications used to treat mast cell disease are strong anticholinergics, like diphenhydramine and doxepin.
- It is not clear if the medications caused dementia or if the conditions that required those medications caused dementia.