scholarly journals Rare occurrence of N-ras point mutations in Philadelphia chromosome positive chronic myeloid leukemia

Blood ◽  
1989 ◽  
Vol 73 (4) ◽  
pp. 1028-1032 ◽  
Author(s):  
SJ Collins ◽  
M Howard ◽  
DF Andrews ◽  
E Agura ◽  
J Radich
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Blast Crisis ◽  
Philadelphia Chromosome ◽  
Point Mutations ◽  
Myelogenous Leukemia ◽  
Nucleotide Sequencing ◽  
Ras Oncogene ◽  
Acute Myelogenous

Point mutations of the N-ras oncogene are relatively common in acute myelogenous leukemia (AML) cells, occurring in some 25% to 50% of patient samples. We used a technique involving the direct nucleotide sequencing of in vitro amplified N-ras genomic fragments to determine the frequency of N-ras point mutations in chronic myeloid leukemia (CML) cells at various stages of the disease. This approach will detect N-ras point mutations in a mixed population of cells if the mutation is present in 25% or more of the cells. We could not demonstrate any point mutation at N-ras codons 12,13 or 59–63 in any of the 44 CML cases analyzed, which included 21 blast crisis samples. In contrast with AML N-ras point mutations are exceedingly rare in CML.

scholarly journals Rare occurrence of N-ras point mutations in Philadelphia chromosome positive chronic myeloid leukemia

Blood ◽  
1989 ◽  
Vol 73 (4) ◽  
pp. 1028-1032 ◽  
Author(s):  
SJ Collins ◽  
M Howard ◽  
DF Andrews ◽  
E Agura ◽  
J Radich
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Blast Crisis ◽  
Philadelphia Chromosome ◽  
Point Mutations ◽  
Myelogenous Leukemia ◽  
Nucleotide Sequencing ◽  
Ras Oncogene ◽  
Acute Myelogenous

Abstract Point mutations of the N-ras oncogene are relatively common in acute myelogenous leukemia (AML) cells, occurring in some 25% to 50% of patient samples. We used a technique involving the direct nucleotide sequencing of in vitro amplified N-ras genomic fragments to determine the frequency of N-ras point mutations in chronic myeloid leukemia (CML) cells at various stages of the disease. This approach will detect N-ras point mutations in a mixed population of cells if the mutation is present in 25% or more of the cells. We could not demonstrate any point mutation at N-ras codons 12,13 or 59–63 in any of the 44 CML cases analyzed, which included 21 blast crisis samples. In contrast with AML N-ras point mutations are exceedingly rare in CML.

Myelodysplastic syndromes and acute leukemia developing after imatinib mesylate therapy for chronic myeloid leukemia

Blood ◽  
2006 ◽  
Vol 108 (8) ◽  
pp. 2811-2813 ◽  
Author(s):  
Craig Kovitz ◽  
Hagop Kantarjian ◽  
Guillermo Garcia-Manero ◽  
Lynne V. Abruzzo ◽  
Jorge Cortes
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chromosomal Abnormalities ◽  
Philadelphia Chromosome ◽  
Myelogenous Leukemia ◽  
Clinical Consequence ◽  
Study Group ◽  
Close Monitoring ◽  
Secondary Myelodysplastic Syndrome ◽  
Acute Myelogenous

AbstractDuring therapy with imatinib, some patients with chronic myeloid leukemia (CML) develop chromosomal abnormalities in Philadelphia chromosome (Ph)-negative cells. These abnormalities are frequently transient and their clinical consequence is unclear. Although some reports have suggested that the abnormalities might be associated with secondary myelodysplastic syndrome (MDS), the diagnosis has not always been established using standard criteria. We report 3 cases of patients treated with imatinib for CML who were subsequently found to have chromosomal abnormalities in Ph-negative cells. One of them developed acute myelogenous leukemia (AML) and the other 2 developed high-risk MDS that rapidly transformed to AML. These cases were identified in a total study group of 1701 patients. Although these occurrences are rare, the findings highlight the need for close monitoring of patients with CML treated with imatinib.

Detection of High Incidence of H-RAS Oncogene Point Mutations in Acute Myelogenous Leukemia

1993 ◽  
Vol 43 (2) ◽  
pp. 151-153 ◽  
Author(s):  
Nobutaka Imamura ◽  
Atsushi Kuramoto ◽  
Hideki Ishihara ◽  
Shoichi Shimizu
Keyword(s):  
Acute Myelogenous Leukemia ◽  
Point Mutations ◽  
Myelogenous Leukemia ◽  
Ras Oncogene ◽  
High Incidence ◽  
Acute Myelogenous

scholarly journals Pathological Fracture: An Unusual Presentation in Childhood Chronic Myeloid Leukemia

2019 ◽  
Vol 13 (4) ◽  
pp. 140
Author(s):  
Mururul Aisyi ◽  
Ayu Hutami Syarif ◽  
Anita Meisita ◽  
Agus Kosasih ◽  
Achmad Basuki ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Pathological Fracture ◽  
Hematological Malignancy ◽  
Blast Crisis ◽  
Philadelphia Chromosome ◽  
Molecular Response ◽  
Invasive Treatment ◽  
Non Invasive ◽  
Blast Count

Introduction: Chronic Myeloid Leukemia is a hematological malignancy driving from myeloproliferative process. It is typified by the presence of the Philadelphia chromosome manifesting in certain distinct complications, including pathological fracture. Pathological fracture is recognized as an extramedullary disease that occurs as a result of transformation of CML into blast crisis phase.Case Presentation: Here, we report a case of pediatric male CML. After being failed with imatinib therapy, he turned to nilotinib and was unable to achieve a major molecular response. He presented with high blast count and pain in the left arm. He was diagnosed with pathological fracture and blast crisis phase CML. Taken the young age and displacement of fracture into consideration, he was conservatively treated by a combination of immobilization and a higher dose of targeted therapy, nilotinib. The 2-month evaluation revealed clinical union and reduction of blast cells.Conclusions: Regarding the minimal displacement and age presentation, pathological fracture in pediatric CML requires non-invasive treatment and optimization of antileukemic therapy.

scholarly journals RAS mutations are rare events in Philadelphia chromosome-negative/bcr gene rearrangement-negative chronic myelogenous leukemia, but are prevalent in chronic myelomonocytic leukemia

Blood ◽  
1990 ◽  
Vol 76 (6) ◽  
pp. 1214-1219 ◽  
Author(s):  
C Hirsch-Ginsberg ◽  
AC LeMaistre ◽  
H Kantarjian ◽  
M Talpaz ◽  
A Cork ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Philadelphia Chromosome ◽  
Point Mutations ◽  
Chronic Phase ◽  
Chronic Myelomonocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Ras Oncogene ◽  
Ras Mutations ◽  
Ras Oncogenes ◽  
Myelomonocytic Leukemia

Abstract Previous reports have indicated that mutations of the RAS oncogenes are not associated with the chronic phase of Philadelphia chromosome- positive chronic myelogenous leukemia (Ph1+ CML). However, further studies were needed to determine their association with Ph1- CML and chronic myelomonocytic leukemia (CMML). Therefore, 6 patients with Ph1- CML who were also negative for BCR rearrangements (Ph1-/BCR- CML) and 30 patients with CMML were analyzed for the presence of RAS oncogene point mutations to determine the similarities of these diseases at the molecular level. The assay used the polymerase chain reaction for amplification of the target RAS sequences and panels of specific synthetic oligonucleotide probes for hybridization to wild type and/or mutated sequences. None of the six Ph1-/BCR- CML patients had mutations in the RAS oncogenes, while 17 of 30 (57%) of the CMML patients had RAS oncogene mutations. Eighty percent of the mutations involved substitution of aspartic acid for glycine (G----A) in the 12th or 13th codons of N-ras or K-ras. Furthermore, although not statistically significant, survival studies raise the possibility of shortened survival in patients with RAS oncogene point mutations, with the average survival being 33 months for Ph1-/BCR- CML, 35 months for CMML without point mutations, and 11 months for CMML with RAS mutations. Thus, RAS mutations appear to be associated with CMML and not Ph1-/BCR- chronic phase CML, there is a high propensity for the K-ras or N-ras mutations to involve an G----A substitution in the 12th or 13th codons, and RAS mutations in CMML may relate to prognosis and require further studies.

α1-Acid glycoprotein expressed in the plasma of chronic myeloid leukemia patients does not mediate significant in vitro resistance to STI571

Blood ◽  
2002 ◽  
Vol 99 (2) ◽  
pp. 713-715 ◽  
Author(s):  
Heather G. Jørgensen ◽  
Moira A. Elliott ◽  
Elaine K. Allan ◽  
Christine E. Carr ◽  
Tessa L. Holyoake ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Plasma Proteins ◽  
Myeloid Leukemia ◽  
Philadelphia Chromosome ◽  
Drug Efficacy ◽  
Acid Glycoprotein ◽  
Proliferation In Vitro ◽  
Normal Controls

Abstract Despite the efficacy of STI571 (Glivec, Novartis, Basle, Switzerland) in treating chronic myeloid leukemia (CML), drug resistance has already been noted both in vitro and in vivo. As plasma proteins, including alpha-1-acid glycoprotein (AGP), may reduce drug efficacy through binding, AGP was investigated for its ability to interact with STI571.  At all stages of CML, AGP plasma level was significantly higher than in normal controls (P < .05). The glycoprotein was purified from normal plasma and individual chronic myeloid leukemia (CML) patients' plasma by low-pressure chromatography. The influence of α1-acid glycoprotein (AGP), in the presence of STI571, on the proliferation of Philadelphia chromosome–positive (Ph+) cells was examined. Normal AGP, even at supraphysiological concentrations, did not block the effect of STI571 on K562-cell proliferation in vitro. Moreover, CML-derived AGP failed to block the effect of STI571 on Ph+ cells in vitro. Thus, these in vitro findings suggest that AGP will not abrogate the antileukemic activity of STI571.

scholarly journals Autografting with cultured marrow in chronic myeloid leukemia: results of a pilot study [see comments]

Blood ◽  
1994 ◽  
Vol 84 (3) ◽  
pp. 724-732 ◽  
Author(s):  
MJ Barnett ◽  
CJ Eaves ◽  
GL Phillips ◽  
RD Gascoyne ◽  
DE Hogge ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Intensive Therapy ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Phase Group ◽  
Cytogenetic Remission ◽  
Group 2 ◽  
Group 1

Abstract Incubation of chronic myeloid leukemia (CML) marrow for 10 days in vitro causes a marked and selective loss of very primitive Philadelphia chromosome (Ph)+ as compared with Ph- progenitors. We have autografted 22 patients with CML (16 in first chronic phase [group 1] and 6 with more advanced disease [group 2]) with marrow treated in this way to facilitate restoration of Ph- hematopoiesis after intensive therapy. Hematologic recovery to greater than 0.5 x 10(9)/L neutrophils occurred in 16 patients, and to greater than 20 x 10(9)/L platelets in 15 of 21 evaluable patients at a median of 29 and 48 days postautograft, respectively. Regenerating marrow cells were 100% Ph- in 13 patients and 75% to 94% Ph- in 3. Between 4 and 36 months (median 12) postautograft, Ph+ cells became detectable in all but 1 (who died in remission) of the 13 patients who achieved complete cytogenetic remission. Four of 7 evaluable patients treated with low-dose interferon alpha were returned to complete cytogenetic remission. Thirteen group 1 patients (81%) are alive 1.0 to 5.7 years (median 2.6) after autografting: 4 in complete cytogenetic remission, 2 in hematologic remission, 6 in chronic phase, and 1 in myeloid blast phase. Three group 2 patients (50%) are alive at 2.6, 3.8, and 4.3 years after autografting: 1 in partial cytogenetic remission, 1 in chronic phase, and 1 in accelerated phase. Thus, autografts of cultured marrow can result in prolonged restoration of Ph- hematopoiesis for some patients with CML.

scholarly journals Phenotypic heterogeneity of primitive leukemic hematopoietic cells in patients with chronic myeloid leukemia

Blood ◽  
1992 ◽  
Vol 80 (10) ◽  
pp. 2522-2530 ◽  
Author(s):  
C Udomsakdi ◽  
CJ Eaves ◽  
PM Lansdorp ◽  
AC Eaves
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Philadelphia Chromosome ◽  
Significant Proportion ◽  
Hematopoietic Cells ◽  
Chronic Phase ◽  
Leukemic Cells ◽  
Clonogenic Cell ◽  
Clonogenic Cells

Abstract The peripheral blood of chronic myeloid leukemia (CML) patients with chronic-phase disease and elevated white blood cell (WBC) counts typically contains markedly increased numbers of a variety of neoplastic pluripotent and lineage-restricted hematopoietic progenitors. These include cells detected in standard colony assays as well as their more primitive precursors. The latter are referred to as long-term culture-initiating cells (LTC-IC) because of their ability to generate clonogenic cell progeny detectable after a minimum of 5 weeks incubation on competent fibroblast feeder layers. In this study, we have investigated a number of the properties of the LTC-IC and clonogenic cells present in the blood of such CML patients with high WBC counts. This included an analysis of the light scattering properties of these progenitors, as well as their expression of CD34 and HLA-DR, Rhodamine-123 staining, and in vitro sensitivity to 4- hydroperoxycyclophosphamide. In the case of LTC-IC, the production of different types of lineage-restricted and multipotent progeny was also analyzed. Most of the circulating LTC-IC and clonogenic cells in the CML patients studied (on average approximately 70% and approximately 90%, respectively) showed features of proliferating or activated cells. This is in marked contrast to the majority of progenitors in the blood of normal individuals and most of the LTC-IC in normal marrow, all of which exhibit a phenotype expected of quiescent cells. Interestingly, a significant proportion of the circulating clonogenic cells and LTC-IC in the CML samples studied (on average approximately 10% and approximately 30%, respectively) appeared to be phenotypically similar to normal circulating progenitors, although their absolute numbers were indicative of a neoplastic origin. Both phenotypes of circulating CML clonogenic cells and LTC-IC could be obtained at approximately 10% to 20% purity by differential multiparameter sorting. These findings suggest that expansion of the Philadelphia chromosome-positive clone at the level of the earliest types of hematopoietic cells results from the activation of mechanisms that enable some, but not all, signals that block the cycling of normal stem cells to be bypassed or overcome. In addition, they provide strategies for purifying these primitive leukemic cells that should facilitate further analysis of the mechanisms underlying their abnormal proliferative behavior.

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