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Nf1 mutant mice with p19ARF gene loss develop accelerated hematopoietic disease resembling acute leukemia with a variable phenotype
Author(s) -
Wiesner Stephen M.,
Geurts Jennifer L.,
Diers Miechaleen D.,
Bergerson Rachel J.,
Hasz Diane E.,
Morgan Kelly J.,
Largaespada David A.
Publication year - 2011
Publication title -
american journal of hematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.456
H-Index - 105
eISSN - 1096-8652
pISSN - 0361-8609
DOI - 10.1002/ajh.22035
Subject(s) - ptpn11 , juvenile myelomonocytic leukemia , cancer research , neuroblastoma ras viral oncogene homolog , leukemia , haematopoiesis , neurofibromin 1 , gene mutation , biology , myelodysplastic syndromes , neurofibromatosis , immunology , mutation , medicine , pathology , bone marrow , genetics , stem cell , gene , kras
Juvenile Myelomonocytic Leukemia (JMML) is a relentlessly progressive myeloproliferative/myelodysplastic (MPD/MDS) hematopoietic disorder more common in patients with any one of at least three distinct genetic lesions, specifically NF1 gene loss and PTPN11 and NRAS mutations. NF1 and PTPN11 are molecular lesions associated with Neurofibromatosis Syndrome Type I (NF1 Syndrome) and Noonan's Syndrome, respectively. The occurrence of JMML is rare; even among those predisposed with these syndromes to development of disease, and secondary genetic events likely contribute to the development and progression of disease. In NF1 syndrome, loss of p53 function is a common event in solid tumors, but uncommon in JMML, suggesting that the p53 pathway may be modified by other events in this hematopoietic disorder. The work presented here investigates the possible role of the p19 Arf ( p19 ) tumor suppressor in development of MPD associated with Nf1 gene loss in mice. We find that Nf1 mutant hematopoietic cells with loss of p19 develop accelerated hematopoietic disease similar to acute leukemia with a variable phenotype. This suggests that p19 may play a role in development of JMML and evaluation of the human p19 homolog ( p14 ARF ) in JMML may be informative. Am. J. Hematol. 86:579–585, 2011. © 2011 Wiley‐Liss, Inc.