The role of Janus Kinase 2 V617F mutation in extramedullary hematopoiesis of the spleen in neoplastic myeloid disorders

• Published in: Modern pathology 2007-09, Vol.20 (9), p.929-935
• Main Authors: Hsieh, Pin-Pen, Olsen, Randy J, O'Malley, Dennis P, Konoplev, Sergej N, Hussong, Jerry W, Dunphy, Cherie H, Perkins, Sherrie L, Cheng, Liang, Lin, Pei, Chang, Chung-Che
• Format: Article
• Language: English
• Subjects: bcl-X Protein - analysis; Biopsy; Bone marrow; Bone Marrow Cells - chemistry; Bone Marrow Cells - enzymology; Chronic Disease; Cloning; Granulocytes; Hematopoiesis, Extramedullary - genetics; Hospitals; Humans; Immunohistochemistry; Janus Kinase 2 - genetics; Janus Kinase 2 - metabolism; Kinases; Laboratory Medicine; Lasers; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - blood; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - enzymology; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemia, Myeloid, Acute - blood; Leukemia, Myeloid, Acute - enzymology; Leukemia, Myeloid, Acute - genetics; Leukemia, Myelomonocytic, Chronic - blood; Leukemia, Myelomonocytic, Chronic - enzymology; Leukemia, Myelomonocytic, Chronic - genetics; Medicine; Medicine & Public Health; Megakaryocytes - chemistry; Megakaryocytes - enzymology; Microdissection - methods; Mutation; Myelodysplastic syndromes; Myelodysplastic Syndromes - blood; Myelodysplastic Syndromes - enzymology; Myelodysplastic Syndromes - genetics; Myeloproliferative Disorders - blood; Myeloproliferative Disorders - enzymology; Myeloproliferative Disorders - genetics; Myeloproliferative Disorders - metabolism; original-article; Pathogenesis; Pathology; Patients; Polycythemia Vera - blood; Polycythemia Vera - enzymology; Polycythemia Vera - genetics; Polymerase Chain Reaction; Primary Myelofibrosis - blood; Primary Myelofibrosis - enzymology; Primary Myelofibrosis - genetics; Proteins; Retrospective Studies; Spleen; Spleen - chemistry; Spleen - enzymology; Stem cells; Thrombocythemia, Essential - blood; Thrombocythemia, Essential - enzymology; Thrombocythemia, Essential - genetics; United States
• ISSN: 0893-3952; 1530-0285
• DOI: 10.1038/modpathol.3800826

Extramedullary hematopoiesis (EMH) in the spleen is a characteristic feature of the chronic myeloproliferative disorders (CMPDs) and various other neoplastic or reactive myeloid conditions. However, the origin of these hematopoietic precursor cells and the molecular mechanisms underlying their development in the spleen is uncertain. The V617F mutation in the Janus Kinase 2 gene ( JAK2 V617F ) was recently shown to be frequently and preferentially present in the peripheral blood and bone marrow cells of CMPD patients, and the resulting dysregulation of its downstream targets is important to CMPD pathogenesis. To determine the occurrence and potential role of JAK2 V617F in splenic EMH cells, we studied splenectomy specimens from 47 patients with significant EMH. JAK2 V617F was detected by real-time PCR melting curve analysis in 22 specimens, including 11/17 chronic idiopathic myelofibrosis, 7/7 polycythemia vera, 1/1 essential thrombocythemia, 1/3 CMPD unclassifiable, 1/5 chronic myelomonocytic leukemia, 0/5 chronic myelogenous leukemia, 1/3 myelodysplastic syndrome and 0/6 acute myeloblastic leukemia cases, whereas only the JAK2 wild-type allele was detected in the other 25. Nineteen of 20 cases with adequate bone marrow samples available for molecular examination demonstrated concordant JAK2 genotypes. Laser-capture microdissection was then used to enrich the EMH and non-EMH splenic cell fractions, confirming that the mutant alleles specifically originated from the EMH cells. Furthermore, megakaryocytes in the JAK2 V617F -positive splenectomy specimens expressed higher levels of Bcl-xL, an antiapoptotic protein and downstream target of the JAK2 / STAT5 pathway. Thus, JAK2 V617F is frequently present in splenic EMH cells associated with CMPD, but it is rarely identified in splenic EMH cells associated with other myeloid disorders. Our results indicate that the precursor cells leading to extramedullary hematopoietic expansion in CMPD most likely originate from the transformed bone marrow clone. Also, dysregulation of downstream pathways such as Bcl-xL may be important to CMPD disease pathogenesis in the spleen.