RAS, FLT3, and TP53 mutations in therapy‐related myeloid malignancies with abnormalities of chromosomes 5 and 7

Oncogenic mutations in the KRAS2, NRAS, or FLT3 gene are detected in more than 50% of patients with de novo acute myeloid leukemia (AML). RAS mutations are also prevalent in de novo myelodysplastic syndrome (MDS), especially chronic myelomonocytic leukemia and juvenile myelomonocytic leukemia. However, few studies have examined these genetic lesions in therapy‐related myeloid malignancies. Monosomy 7/del(7q) and monosomy 5/del(5q) represent the most common cytogenetic abnormalities in therapy‐related MDS and AML (t‐MDS/t‐AML) and are strongly associated with prior exposure to alkylating agents. Mutational analysis of bone marrow specimens from a well‐characterized cohort of 26 t‐MDS/t‐AML patients with abnormalities of chromosomes 5 and/or 7 revealed 3 with RAS mutations. Further analyses of 23 of these cases uncovered one FLT3 internal tandem duplication and five TP53 mutations. The four patients with RAS or FLT3 mutations had monosomy 7, including one with abnormalities of chromosomes 5 and 7. One specimen demonstrated mutations in both KRAS2 and TP53. RAS and FLT3 mutations, which are thought to stimulate the proliferation of leukemia cells, appear to be less common in t‐MDS/t‐AML than in de novo AML, whereas TP53 mutations are more frequent. © 2004 Wiley‐Liss, Inc.

[1]  Sonali M. Smith,et al.  Clinical-cytogenetic associations in 306 patients with therapy-related myelodysplasia and myeloid leukemia: the University of Chicago series. , 2003, Blood.

[2]  J. Downing,et al.  Acute leukemia: a pediatric perspective. , 2002, Cancer cell.

[3]  Zhijian Qian,et al.  Expression profiling of CD34+ hematopoietic stem/ progenitor cells reveals distinct subtypes of therapy-related acute myeloid leukemia , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[4]  G. Ehninger,et al.  Analysis of Flt3-activating Mutations in 979 Patients with Acute Myelogenous Leukemia: Association with Fab Subtypes and Identification of Subgroups with Poor Prognosis , 2022 .

[5]  D. Gilliland,et al.  Focus on acute leukemias. , 2002, Cancer cell.

[6]  Soyoung Lee,et al.  A Senescence Program Controlled by p53 and p16INK4a Contributes to the Outcome of Cancer Therapy , 2002, Cell.

[7]  S. Lowe,et al.  Dissecting p53 tumor suppressor functions in vivo. , 2002, Cancer cell.

[8]  M. Andersen,et al.  Genetic pathways in therapy-related myelodysplasia and acute myeloid leukemia. , 2002, Blood.

[9]  Gideon Bollag,et al.  GTPase activating proteins: critical regulators of intracellular signaling. , 2002, Biochimica et biophysica acta.

[10]  J. Downing,et al.  Expression of a conditional AML1-ETO oncogene bypasses embryonic lethality and establishes a murine model of human t(8;21) acute myeloid leukemia. , 2002, Cancer cell.

[11]  D. Christiansen,et al.  Internal tandem duplications of the FLT3 and MLL genes are mainly observed in atypical cases of therapy-related acute myeloid leukemia with a normal karyotype and are unrelated to type of previous therapy , 2001, Leukemia.

[12]  E. Green,et al.  Candidate gene isolation and comparative analysis of a commonly deleted segment of 7q22 implicated in myeloid malignancies. , 2001, Genomics.

[13]  J. Radich,et al.  FLT3, RAS, and TP53 mutations in elderly patients with acute myeloid leukemia. , 2001, Blood.

[14]  D. Christiansen,et al.  Mutations with loss of heterozygosity of p53 are common in therapy-related myelodysplasia and acute myeloid leukemia after exposure to alkylating agents and significantly associated with deletion or loss of 5q, a complex karyotype, and a poor prognosis. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  N. Zhao,et al.  Transcript map and comparative analysis of the 1.5-Mb commonly deleted segment of human 5q31 in malignant myeloid diseases with a del(5q). , 2001, Genomics.

[16]  W. Berdel,et al.  Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways. , 2000, Blood.

[17]  S. Lowe,et al.  Genetic analysis of chemoresistance in primary murine lymphomas , 2000, Nature Medicine.

[18]  T. Naoe,et al.  Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines , 2000, Oncogene.

[19]  M. Taniwaki,et al.  Distinct genetic involvement of the TP53 gene in therapy-related leukemia and myelodysplasia with chromosomal losses of Nos 5 and/or 7 and its possible relationship to replication error phenotype , 1999, Leukemia.

[20]  M. Veigl,et al.  Mice over-expressing human O6alkylguanine-DNA alkyltransferase selectively reduce O6methylguanine mediated carcinogenic mutations to threshold levels after N-methyl-N-nitrosourea , 1999, Oncogene.

[21]  T. Jacks,et al.  Myeloid malignancies induced by alkylating agents in Nf1 mice. , 1999, Blood.

[22]  T. Naoe,et al.  Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. , 1999, Blood.

[23]  T. Naoe,et al.  Molecular evolution of acute myeloid leukaemia in relapse: unstable N‐ras and FLT3 genes compared with p53 gene , 1999, British journal of haematology.

[24]  I. Weissman,et al.  A PMLRARα transgene initiates murine acute promyelocytic leukemia , 1997 .

[25]  S. Ben-Neriah,et al.  Microsatellite instability and p53 mutations in therapy-related leukemia suggest mutator phenotype. , 1996, Blood.

[26]  R. Larson,et al.  Activating RAS mutations in therapy-related myeloid disorders associated with deletions of chromosomes 5 and 7. , 1996 .

[27]  E. Green,et al.  Cytogenetic and molecular delineation of a region of chromosome 7 commonly deleted in malignant myeloid diseases. , 1996, Blood.

[28]  T. Rabbitts,et al.  An Mll–AF9 Fusion Gene Made by Homologous Recombination Causes Acute Leukemia in Chimeric Mice: A Method to Create Fusion Oncogenes , 1996, Cell.

[29]  R. Larson,et al.  Therapy-related myeloid leukemia. , 2008, Seminars in oncology.

[30]  D. Largaespada,et al.  Nf1 deficiency causes Ras-Dediated granulocyte/macrophage colony stimulating factor hypersensitivity and chronic myeloid leukaemia , 1996, Nature Genetics.

[31]  G. Mufti,et al.  Possible co-existence of RAS activation and monosomy 7 in the leukaemic transformation of myelodysplastic syndromes. , 1995, Leukemia research.

[32]  T. Koh,et al.  N-ras mutation in 7,12-dimethylbenz[a]anthracene (DMBA)-induced erythroleukemia in Long-Evans rats. , 1995, Cancer letters.

[33]  E. Wattel,et al.  Myelodysplastic syndromes and acute myeloid leukemia with 17p deletion. An entity characterized by specific dysgranulopoïesis and a high incidence of P53 mutations. , 1995, Leukemia.

[34]  K. Shannon,et al.  Genetic analysis is consistent with the hypothesis that NF1 limits myeloid cell growth through p21ras , 1994 .

[35]  S. Gerson,et al.  Rapid repair of O6-methylguanine-DNA adducts protects transgenic mice from N-methylnitrosourea-induced thymic lymphomas. , 1994, Cancer research.

[36]  C. Denny,et al.  Chronic myelomonocytic leukemia: Tel-a-kinase what Ets all about , 1994, Cell.

[37]  P. O'Connell,et al.  Loss of the normal NF1 allele from the bone marrow of children with type 1 neurofibromatosis and malignant myeloid disorders. , 1994, The New England journal of medicine.

[38]  R. Espinosa,et al.  Cytogenetic and molecular delineation of the smallest commonly deleted region of chromosome 5 in malignant myeloid diseases. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[39]  S. Gerson,et al.  The prevention of thymic lymphomas in transgenic mice by human O6-alkylguanine-DNA alkyltransferase. , 1993, Science.

[40]  C. Bloomfield,et al.  ras oncogene activation and occupational exposures in acute myeloid leukemia. , 1992, Journal of the National Cancer Institute.

[41]  P. O'Connell,et al.  Monosomy 7 myeloproliferative disease in children with neurofibromatosis, type 1: epidemiology and molecular analysis. , 1992, Blood.

[42]  R. Berger,et al.  P53 gene mutations in acute myeloid leukemia with 17p monosomy. , 1991, Blood.

[43]  K. Tanaka,et al.  Cytogenetic and molecular changes in leukemia among atomic bomb survivors. , 1991, Journal of radiation research.

[44]  E. Liu,et al.  Mutations of the ras proto-oncogenes in childhood monosomy 7. , 1991, Blood.

[45]  G. Daley,et al.  Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. , 1990, Science.

[46]  C. Bartram,et al.  Point mutation of the ras protooncogenes and chromosome aberrations in acute nonlymphocytic leukemia and preleukemia related to therapy with alkylating agents. , 1988, Cancer research.

[47]  R. Larson,et al.  Clinical and cytogenetic correlations in 63 patients with therapy-related myelodysplastic syndromes and acute nonlymphocytic leukemia: further evidence for characteristic abnormalities of chromosomes no. 5 and 7. , 1986, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[48]  J. Rowley,et al.  Acute leukemia after treatment of lymphoma. , 1977, The New England journal of medicine.

[49]  Jennifer Clark,et al.  Comprehensive genotypic analysis of leukemia: clinical and therapeutic implications. , 2002, Current opinion in oncology.

[50]  D. Gilliland,et al.  FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myeloproliferative disease in a murine bone marrow transplant model. , 2002, Blood.

[51]  J. Radich,et al.  FLT 3 , RAS , and TP 53 mutations in elderly patients with acute myeloid leukemia , 2001 .

[52]  早川 文彦.  Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines , 2000 .

[53]  I. Weissman,et al.  A PMLRARalpha transgene initiates murine acute promyelocytic leukemia. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[54]  J. Maris,et al.  Monosomy 7 myelodysplastic syndrome and other second malignant neoplasms in children with neurofibromatosis type 1. , 1997, Cancer.

[55]  J. Pedersen‐Bjergaard.  Radiotherapy- and chemotherapy-induced myelodysplasia and acute myeloid leukemia. A review. , 1992, Leukemia research.

[56]  T. Sekiya,et al.  Detection of ras gene mutations in human lung cancers by single-strand conformation polymorphism analysis of polymerase chain reaction products. , 1990, Oncogene.