Sep. 22, 2006 Molecular Basis of Myeloproliferative

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Sep. 22, 2006 Molecular Basis of
Myeloproliferative Disorders
Stuart Kornfeld
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Case 1 P.W., a 77 y/o man, with a history of
venous thromboembolism and polycythemia, was
referred in 9/04 for evaluation. In April, 2003,
he was hospitalized with a pulmonary embolism and
DVT. Treatment included IVC filter placement and
anticoagulation, including long-term coumadin.
He used oxygen intermittently for exertional
hypoxia since then. A CBC in August 2004 reveals
Hgb 18.2, Hct 57, WBC 6,900 and plts 745,000, so
he was referred to M.B. On exam, no splenomegaly
was noted. Lab data included Epo 1.8, ferritin
18, and normal pO2 at rest. In view of low EpO
level, dx of P. Vera favored over polycythemia 2º
to hypoxia. Treatment consisted of phlebotomy,
an aspirin per day and continuation of the
coumadin. By 3/05, Hgb 15.5, Hct 48.7, and Plts.
764,000. His platelet count gradually increased
to 1,177,000 on 1/06 and Hydrea started. His
last visit was 6/06 with CBC showing Hgb 10.5,
WBC 4800, and plts. 355,000. On 1/06 visit,
blood was collected for JAK-2 mutation analysis.
Genomic DNA was extracted and a PCR-based assay
performed for the point mutation causing JAK-2 V
617 F. It was positive for mutation.
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Case 2 J.M., a 67 y/o man, was referred to M.B.
in 10/04 for follow-up care of a
myeloproliferative disorder. The HPI began in
12/03 when a pre-op CBC showed WBC 24,300, Hgb
13.9, and plts. 1,167,000. Other lab tests were
normal. PE unremarkable. No palpable
hepatosplenomegaly. B.M. showed increased
cellulocity of 65-75, normal ME ratio, minimal
focal fibrosis and atypical megakaryocytes.
Cytogenetics and BCR-ABl studies were normal. Dx
was myeloproliferative disorder essential
thrombocythemia vs. early myelofibrosis. The
high plt. Count and lack of splenomegaly favored
ET whereas atypical megakarytocytes favored
prefibrotic stage of chromic idiopathic
myelofibrosis. Pt. Started on Anagrelide and
plts. Decreased to 332,000 by 7/04 with stable
Hgb and WBC of 15,900. He then moved to St.
Louis.Course Pt. Continued to do well.
Possibility of switching from Anagrelide to
Hydrea considered in view of recent data showing
that Anagrelide associated with increased risk of
venous thrombotic events and a slightly increased
risk of myelofibrosis. It was decided not to
change drug since he was doing so well. On 1/06
visit, blood collected for JAK-2 mutation
analysis. It was positive for the JAK2 V617F
mutation.
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William Dameshek
Blood 6,372- (1951)
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JCI 59, 841- (1977)
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NEJ 352, 17 (2005)
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Nature 434, 1144-1148 (2005)
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P vera patients have a V617F Mutation in JAK2
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FIGURE 3. Mutated JAK2 induces constitutive
signalling leading to growth factor independence.
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NEJ 352, 17 (2005)
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PNAS 103, 6224- (2006)
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• Some Remaining Questions
• How can one mutation give rise to three
  disorders?
• - Accumulation of additional genetic
  alterations?
• - Cell specific factors that modulate JAK2
  action?
• JAK2 has signaling role in other systems,
  including leptin receptor, GH receptor, and
  interleukin receptors. Will disorders of fat
  metabolism, body growth, and the immune system
  arise from mutations in JAK2?
• What is the cause of the myeloproliferative
  syndromes in patients who lack the JAK2 mutation?
  Other mutations in JAK/STAT pathway?
• Will inhibition of the mutant JAK2 on downstream
  effectors be useful therapeutic agents?
• BJ now offer molecular test for the JAK2 V617F
  mutation (Contact Jeanne Anderson (4-7601),
  Molecular Diagnostic Lab (4-8685) or the
  molecular pathology fellow (4-1881).