Paroxysmal nocturnal hemoglobinuria and concurrent JAK2(V617F) mutation

Autor: Kenneth H. Shain, Ramon V. Tiu, Gisela Caceres, Manuel G. Afable, D J Araten, Michael J. Clemente, Jaroslaw P. Maciejewski, Christine L. O'Keefe, Lubomir Sokol, Zhang Lm, Chiharu Sugimori, Eric Padron, J M Lee, Alan F. List, Pearlie K. Epling-Burnette
Rok vydání: 2012
Předmět:
Zdroj: Blood Cancer Journal
ISSN: 2044-5385
Popis: Paroxysmal nocturnal hemoglobinuria (PNH) is a hemolytic and pro-thrombotic disorder associated with the clonal expansion of hematopoietic stem cells harboring somatic mutations in the PIG-A gene.1 Mutations in PIG-A result in a lack of surface expression of all glycosylphosphatidylinositol (GPI)-anchored proteins, including the complement inhibitors CD55 and CD59,2 which is responsible for the hemolytic (and probably also the pro-thrombotic) phenotype.3, 4 However, long-term colony-forming assays and in vivo murine models have failed to show that PIG-A mutations are alone sufficient to drive clonal expansion.5, 6 There are two leading hypotheses to account for clonal expansion of PIG-A-null stem cells: (i) clonal selection and (ii) second mutations. The first model posits that aplastic anemia—which is epidemiologically associated with PNH—results in an immune-mediated marrow injury that selectively spares PNH stem cells.7 The second hypothesis is borrowed from models of oncogenesis and may be supported by the observation that patients with PNH can harbor clonal cytogenetic abnormalities.8 However, no specific gene mutations other than PIG-A have been reported in patients with PNH—with one exception. In two patients, a rearrangement of chromosome 12 with a break in the 3′-untranslated region of the HMGA2 gene has been reported.9 Overexpression of an HMGA2 truncated protein recapitulates an myeloproliferative neoplasms (MPN)-like phenotype in a murine model and could theoretically contribute to clonal expansion in PNH.10 Interestingly, literature from the 1970's has reported several cases of PNH in association with myelofibrosis and other MPNs.11, 12 Here we report on three index cases of PNH with myeloproliferative features harboring a JAK2V617F mutation, which is now understood to drive clonal expansion in many MPNs.13 The first case is a 51-year-old male, presenting with right hemiparesis and dysarthria secondary to a stroke, followed by multiple thrombotic events, including the Budd Chiari Syndrome (BCS). A hypercoagulable workup revealed the presence of the JAK2V617F mutation in the peripheral blood. Upon referral to us, a complete blood count noted an Hgb of 5 g/dl, platelets (PLTs) of 492 × 109/l and a white blood cell (WBC) 8.90 × 109/l. Bone marrow biopsy revealed a hypercellular marrow (80–100%), dysmegakaryopoiesis, a 4% myeloblast population and normal cytogenetics (Figure 1). The patient later presented with an elevated lactate dehydrogenase (LDH) and undetectable haptoglobin. Flow cytometry revealed that 99% of the granulocytes and 13% of the erythrocytes were GPI (−), confirming the diagnosis of PNH, and the patient was initiated on eculizumab. Although he has been transfusion independent for 3 years with this therapy, he has had multiple complications of BCS, including esophageal variceal hemorrhage. Figure 1 Morphological features of the bone marrow in patients with PNH and the JAK2V617F mutation. Patient 1: (i) hematoxilin–eosin-stained section showing hyperplasia and mild dysplasia. (ii) Anti-factor VIII section showing increased number of megakaryocytes ... The second patient, a 65-year-old male, presented with darkened urine and transfusion-dependent anemia, and was found to have 40% PNH red cells. At that time, hematological parameters were: WBC 6.7 × 109/l, 76.7% granulocytes Hgb 95 g/l and PLTs 580 × 109/l. His LDH was nine-fold the upper limit of normal. Two years later, despite prophylactic anticoagulation with coumadin, he developed a splenic infarction, prompting a splenectomy. His WBC then rose to over 100 000 × 109/l and his PLT count to over 1 000 000 × 109/l, and the JAK2V617F mutation was identified. He developed a post-operative portal vein thrombosis, and he was treated at that time with hydroxyurea, oral anticoagulation and eculizumab. Ten months later, he developed BCS in the setting of a therapeutic international normalized ratio, but low trough eculizumab levels; BCS completely resolved with intravenous tissue plasminogen activator, and he was started on aspirin, fondaparinux and hydroxyurea—and a shorter eculizumab-dosing interval. He then developed a progressively increasing WBC, and the marrow demonstrated hypercellularity, granulocytic hyperplasia and moderate reticulin fibrosis (Figure 1), and a 46, XY, del (17) (p11) (18/24) karyotype. Three additional metaphases demonstrated the del17 abnormality with a non-clonal additional abnormality in each case. He was given decitabine, but expired 4 years after the diagnosis of PNH secondary to progressive liver failure due to iron overload. The third patient is a 78-year-old male with a history of prostate cancer in 2004, treated with brachytherapy. He also had a history of arthritis, pulmonary hypertension and cutaneous melanoma. In 2003, he was mildly anemic, and in 2006, a marrow examination revealed hypercellularity without excess blasts. In 2009, he noticed dark urine; the Hgb was 102 g/l with 4.5% reticulocytes, PLTs 648 × 109/l, WBC 10.1 × 109/l, 77% polys, 15% lymphocytes and 7% monocytes. The LDH was 1367 IU/L (normal
Databáze: OpenAIRE
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