Ras activation in myelodysplastic syndromes: clinical and molecular study of the chronic phase of the disease

Melani, Cecilia; Haliassos, A.; Chomel, Jean‐Claude; Miglino, Maurizio; Ferraris, Anna Maria; Gaetani, Gian Franco; Kaplan, Jean Claude; Kitzis, Alain

doi:10.1111/j.1365-2141.1990.tb06327.x

Cited by 33 publications

(7 citation statements)

References 21 publications

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“…We therefore longitudinally investigated ras gene m uta tion from MDS and AML by using a polymerase chain reaction (PCR) method. Like recent reports [9][10][11], we found a relatively high incidence of multiple point m uta tions of ras genes and also found diversity of such m uta tions during disease progression. Since somatic mutations of the ras gene have been postulated to serve as clonal markers of hematopoietic neoplasms [ 12], our cases carry ing multiple point mutations of the ras gene may help to understand the mechanisms of clonal evolution of myeloid neoplasms.…”

Section: Introductionsupporting

confidence: 70%

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Multiple Point Mutation of N-ras and K-ras Oncogenes in Myelodysplastic Syndrome and Acute Myelogenous Leukemia

Nakagawa

S²,

Imoto³

et al. 1992

Oncology

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We analyzed activating mutations of N-ras and K-ras by the polymerase chain reaction and oligonucleotide hybridization in hematological disorders. Activating mutations of these codons were detected in 4 of 20 cases of myelodysplastic syndrome (MDS) and 15 of 77 cases of acute myelogenous leukemia (AML). Out of 19 cases of MDS and AML who carried active mutations, 7 cases were found to have two or more distinct mutations in activating codons of N-ras and K-ras. Ras mutation was found preferentially in progressive disease such as refractory anemia with excess of blasts (RAEB) of RAEB in transformation (RAEB-t). A relatively high incidence of ras mutation was found in M₅ AML (40%). No ras mutations were found in other hematological disorders, such as acute lymphoblastic leukemia and chronic myelogenous-leukemia. The most frequent amino acid substitution was that of an aspartate for glycine at codon 12 of N-ras resulting from G to A mutation (11/35). The survival of AML patients who carried ras mutations showed no significant differences from those without ras mutations calculated by Kaplan-Meier. Seven cases of MDS and 7 cases of AML patients could be investigated at various points during their clinical course. Among these 14 cases, we found 2 interesting cases of MDS. The first case lost multiple clones carrying ras mutations during disease progression, the second case acquired mutation of the ras gene during disease progression. These results suggested that multiple point mutations of ras genes may not be initiating events but may contribute to a clonal evolution of MDS and AML.

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Section: Introductionsupporting

confidence: 70%

“…Several papers already described multiple point m uta tions of ras genes in MDS and AML [9][10][11]. In this study we commonly found multiple point mutations of ras genes (7 cases out of 19; table 2).…”

Section: Discussionmentioning

confidence: 53%

Multiple Point Mutation of N-ras and K-ras Oncogenes in Myelodysplastic Syndrome and Acute Myelogenous Leukemia

Nakagawa

S²,

Imoto³

et al. 1992

Oncology

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“…Furthermore, analysis by ASRA will not be affected by double mutations on one allele, whereas they can interfere with analysis by A S 0 hybridization [20]. The presence of double mutations in N-ras appears be a general phenomenon in hematopoietic malignancies with reports in AML [l], ALL [21], MDS [6,22], and multiple myeloma [23], but their importance in the clinical course of these diseases has not been addressed.…”

Section: Discussionmentioning

confidence: 99%

Analysis of N‐ras gene mutations in acute myeloid leukemia by allele specific restriction analysis

et al. 1991

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N-ras gene activation occurs via single base substitutions in codons 12, 13, and 61. We have developed a rapid screening method, termed allele specific restriction analysis (ASRA), for detection of N-ras mutations at these three critical codons in acute myeloid leukemia (AML). Patient DNA samples are amplified by the polymerase chain reaction (PCR) by using primers that induce restriction sites in normal but not mutant N-ras alleles. We have used ASRA to identify 5 point mutations in four out of 19 patients at initial presentation of de novo AML. Three patients had one mutation at codon 12, 13, or 61 respectively, while a fourth patient had concurrent mutations at codons 12 and 13. N-ras mutations were more common in patients over 65 years of age (P less than 0.04), but did not correlate with FAB classification, attainment of complete remission, disease free survival, or overall survival. ASRA can also be used as the first step in a more sensitive approach to the detection of ras mutations. When ASRA was combined with allele specific oligonucleotide (ASO) hybridization the sensitivity and specificity of these assays were increased. This allowed identification of additional low level mutations in two patients. The data presented here constitute the first complete analysis of N-ras mutations in leukemia by ASRA and include the first identification of three concurrent N-ras mutations in a single leukemic patient. By facilitating sensitive sequential studies, ASRA should contribute to our understanding of the role of N-ras mutations in leukemogenesis.

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“…Factors predicting shorter survival include older age, anemia, neutropenia, thrombocytopenia, high percentage of bone marrow blasts, extensive dyspoiesis, abnormal central clustering of immature precursors within the bone marrow (ALIP score), increased numbers of circulating CD34 cells [7-9, 11, 14-20], abnormal cytogenetics (particularly involving chromosomes 5 and 7) [21], secondary MDS, expression of the mdr-1 phenotype [22], and RAS oncogene mutations or activation [23][24][25][26]. The relevance of p53 mutations is under study [27].…”

Section: Introductionmentioning

confidence: 99%

The Myelodysplastic Syndromes

Cheson

1997

The Oncologist

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The myelodysplastic syndromes (MDS) are a heterogeneous group of disorders characterized by peripheral blood cytopenias with a hypercellular bone marrow exhibiting dyspoiesis. The MDS range from those with a relatively indolent course (e.g., refractory anemia with or without ringed sideroblasts) to more aggressive disorders (e.g., refractory anemia with excess blasts [RAEB], and RAEB in transformation [RAEB‐T]), which may exhibit a clinical course indistinguishable from acute myeloid leukemia (AML). Supportive care is the standard treatment for most patients, particularly those who are elderly, with the judicious use of blood components and antibiotics. For younger patients with RAEB and RAEB‐T, antileukemic therapy might be considered, since the outcome is similar to that of patients with AML. Promising new chemotherapy agents currently in clinical trials include the topoisomerase I inhibitor, topotecan. The only curative treatment for MDS is allogeneic bone marrow transplantation, with long‐term survival in approximately 40%, but with treatment‐related deaths in 25%‐40%. Factors predicting outcome include age, cytogenetics, number of blasts, and others. Myeloid growth factors (e.g., G‐CSF, GM‐CSF), increase the granulocyte count in most patients and may be useful in the setting of an active infection, although the prophylactic use of these agents does not improve survival. Erythropoietin increases the hematocrit in about 20% of patients. Growth factors being evaluated for their role in enhancing platelet counts include interleukin 11, stem cell factor, and megakaryocyte growth and development factor (thrombopoietin). Newer strategies to improve the outcome of patients with MDS should be based on an increased understanding of the biology of these disorders.

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Ras activation in myelodysplastic syndromes: clinical and molecular study of the chronic phase of the disease

Cited by 33 publications

References 21 publications

Multiple Point Mutation of N-<i>ras</i> and K-<i>ras</i> Oncogenes in Myelodysplastic Syndrome and Acute Myelogenous Leukemia

Multiple Point Mutation of N-<i>ras</i> and K-<i>ras</i> Oncogenes in Myelodysplastic Syndrome and Acute Myelogenous Leukemia

Analysis of N‐ras gene mutations in acute myeloid leukemia by allele specific restriction analysis

The Myelodysplastic Syndromes

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