A Unique, Complex Variant Philadelphia Chromosome Translocation in a Patient With Typical Chronic Myelogenous Leukemia

2001 ◽  
Vol 125 (3) ◽  
pp. 437-439
Author(s):  
Raida Oudat ◽  
Zebunnisa Khan ◽  
Armand B. Glassman
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Chromosomal Abnormalities ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Chromosome Translocation ◽  
Chromosome 9 ◽  
Myelogenous Leukemia ◽  
Chromosome 11 ◽  
Ph Chromosome ◽  
Conventional Cytogenetics

Abstract The Philadelphia (Ph) chromosome [der(22) t(9;22)(q34;q11)] is the characteristic chromosomal abnormality found in chronic myelogenous leukemia (CML). This chromosome has been reported in patients with other chromosomal abnormalities. In this study, we describe a patient with hematologically typical chronic-phase CML with an unusual and complex translocation involving chromosomes 9, 11, and 22. These complex translocations were identified by G-banded conventional cytogenetics and confirmed by fluorescence in situ hybridization (FISH) using whole chromosome painting probes (wcp). To the best of our knowledge, these are unique translocations involving the short and the long arms of chromosome 9 in 4 different translocations with the short arm of chromosome 11 and the long arm of chromosome 22.

scholarly journals Consistent amounts of acute leukemia-associated P190BCR/ABL transcripts are expressed by chronic myelogenous leukemia patients at diagnosis

Blood ◽  
1996 ◽  
Vol 87 (3) ◽  
pp. 1075-1080 ◽  
Author(s):  
G Saglio ◽  
F Pane ◽  
E Gottardi ◽  
F Frigeri ◽  
MR Buonaiuto ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Chronic Myelogenous Leukemia ◽  
Lymphoblastic Leukemia ◽  
Quantitative Polymerase Chain Reaction ◽  
Chronic Phase ◽  
Chromosome Translocation ◽  
Myelogenous Leukemia ◽  
Absolute Amount ◽  
Ph Chromosome ◽  
Peripheral Cells

In chronic myelogenous leukemia (CML), the Philadelphia (Ph) chromosome translocation results in the formation of BCR/ABL genes, normally transcribed in two types of hybrid transcripts with a b2a2 or b3a2 BCR/ABL junction, which give origin to 210-kD fusion proteins (P210). A third type of BCR/ABL (with e1a2 type of junction) has been identified in approximately 50% of the Ph-positive acute lymphoblastic leukemia (Ph+ALL) cases and results in the production of a BCR/ABL protein of 190 kD (P190). The presence of this transcript has been associated almost exclusively with the presence of an acute leukemia phenotype. By contrast, here we describe that in addition to transcripts with the b2a2 and b3a2 types of junction corresponding to the P210 proteins, virtually all CMLs at diagnosis bear also BCR/ABL transcripts showing the e1a2 type of junction, which correspond to the acute leukemia- associated P190 protein. With a quantitative polymerase chain reaction assay we found that the amount of the e1a2 mRNA present in CMLs in chronic phase, although in absolute amount much lower than that present in Ph+ ALLs, represents in most cases approximately 20% to 30% of the total BCR/ABL transcripts. Moreover, using a novel and very sensitive Western blot technique, we detected relevant amounts of P190 protein in addition to P210 from peripheral cells of two of the patients.

scholarly journals C-sis and C-abl expression in chronic myelogenous leukemia and other hematologic malignancies

Blood ◽  
1986 ◽  
Vol 67 (3) ◽  
pp. 839-841
Author(s):  
P Romero ◽  
M Blick ◽  
M Talpaz ◽  
E Murphy ◽  
J Hester ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Chromosomal Rearrangements ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Hematologic Malignancies ◽  
Chromosome 9 ◽  
Myelogenous Leukemia ◽  
Chromosome 22 ◽  
Aberrant Expression

Cellular oncogenes have been localized at the breakpoints of characteristic chromosomal rearrangements occurring in certain hematologic malignancies. This has been reported to result in aberrant expression of the involved oncogenes. Over 90% of chronic myelogenous leukemia (CML) is characterized by a reciprocal translocation that brings c-abl from chromosome 9 to chromosome 22, and c-sis from chromosome 22 to chromosome 9. To investigate the possible role of these two oncogenes in the leukemic process, we studied their expression in a number of fresh samples obtained from patients with various forms of leukemia, by Northern blot analysis using c-onc probes. Seven of 24 samples obtained from patients with either CML or chronic myelomonocytic leukemia expressed a normal 4.0-kilobase (kb) c- sis transcript. C-sis expression was found only in the accelerated/blast phases but not in the chronic phase of CML. All of the CML Philadelphia chromosome-positive (Ph1+) samples expressed an aberrant 8-kb c-abl transcript. The expression of c-sis in

scholarly journals C-sis and C-abl expression in chronic myelogenous leukemia and other hematologic malignancies

Blood ◽  
1986 ◽  
Vol 67 (3) ◽  
pp. 839-841 ◽  
Author(s):  
P Romero ◽  
M Blick ◽  
M Talpaz ◽  
E Murphy ◽  
J Hester ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Chromosomal Rearrangements ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Hematologic Malignancies ◽  
Chromosome 9 ◽  
Myelogenous Leukemia ◽  
Chromosome 22 ◽  
Aberrant Expression

Abstract Cellular oncogenes have been localized at the breakpoints of characteristic chromosomal rearrangements occurring in certain hematologic malignancies. This has been reported to result in aberrant expression of the involved oncogenes. Over 90% of chronic myelogenous leukemia (CML) is characterized by a reciprocal translocation that brings c-abl from chromosome 9 to chromosome 22, and c-sis from chromosome 22 to chromosome 9. To investigate the possible role of these two oncogenes in the leukemic process, we studied their expression in a number of fresh samples obtained from patients with various forms of leukemia, by Northern blot analysis using c-onc probes. Seven of 24 samples obtained from patients with either CML or chronic myelomonocytic leukemia expressed a normal 4.0-kilobase (kb) c- sis transcript. C-sis expression was found only in the accelerated/blast phases but not in the chronic phase of CML. All of the CML Philadelphia chromosome-positive (Ph1+) samples expressed an aberrant 8-kb c-abl transcript. The expression of c-sis in

scholarly journals Association of a chromosomal 3;21 translocation with the blast phase of chronic myelogenous leukemia

Blood ◽  
1987 ◽  
Vol 70 (5) ◽  
pp. 1338-1342 ◽  
Author(s):  
CM Rubin ◽  
RA Larson ◽  
MA Bitter ◽  
JJ Carrino ◽  
MM Le Beau ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Reciprocal Translocation ◽  
Clonal Evolution ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Cytogenetic Abnormality ◽  
Blast Phase ◽  
Male Patients

Abstract An identical reciprocal translocation between the long arms of chromosomes 3 and 21 with breakpoints in bands 3q26 and 21q22, t(3;21)(q26;q22), was found in three male patients with the blast phase of chronic myelogenous leukemia (CML). The abnormality was clonal in all three patients and was always accompanied by either a standard or variant 9;22 translocation resulting in a Philadelphia chromosome (Ph1). In two cases, the t(3;21) was the only abnormality other than a t(9;22) in the primary clone. Serial studies of one patient demonstrated that the t(3;21) occurred as a result of clonal evolution near the time of development of the blast phase. We have not observed the t(3;21) in greater than 500 patients with CML in the chronic phase. Thus, the t(3;21) is a new recurring cytogenetic abnormality associated with the blast phase of CML.

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.

scholarly journals Detection by enzymatic amplification of bcr-abl mRNA in peripheral blood and bone marrow cells of patients with chronic myelogenous leukemia

Blood ◽  
1989 ◽  
Vol 73 (6) ◽  
pp. 1735-1741 ◽  
Author(s):  
W Lange ◽  
DS Snyder ◽  
R Castro ◽  
JJ Rossi ◽  
KG Blume
Keyword(s):  
Bone Marrow ◽  
Chronic Myelogenous Leukemia ◽  
Peripheral Blood ◽  
Bone Marrow Cells ◽  
Philadelphia Chromosome ◽  
Chromosome 9 ◽  
Myelogenous Leukemia ◽  
Enzymatic Amplification ◽  
Polymerase Chain ◽  
Marrow Cells

Abstract The Philadelphia chromosome of chronic myelogenous leukemia (CML) patients is caused by a translocation of the c-abl gene from chromosome 9 to the breakpoint cluster region (bcr) on chromosome 22. A new bcr- abl mRNA is expressed in these cases. We have developed a modified polymerase chain reaction (PCR) for the detection of this mRNA. The method is extremely sensitive, reliable, and relatively fast. The analysis of peripheral blood or bone marrow cells from CML patients treated with chemotherapy shows that the two possible mRNAs are expressed in various combinations. Our results show that even after myeloablative therapy for bone marrow transplantation bcr-abl mRNAs are still expressed. Further studies, however, are necessary to determine the clinical relevance of a small number of persisting cells expressing the bcr-abl mRNA.

scholarly journals Multi-unit ribozyme-mediated cleavage of bcr-abl mRNA in myeloid leukemias

Blood ◽  
1995 ◽  
Vol 85 (8) ◽  
pp. 2162-2170 ◽  
Author(s):  
LH Leopold ◽  
SK Shore ◽  
TA Newkirk ◽  
RM Reddy ◽  
EP Reddy
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Fusion Gene ◽  
Folate Receptor ◽  
Philadelphia Chromosome ◽  
Chromosome 9 ◽  
Myelogenous Leukemia ◽  
Myeloid Leukemias ◽  
Transforming Activity ◽  
Cleavage Reactions

Chronic myelogenous leukemia is characterized by the Philadelphia chromosome, which at the molecular level results from the fusion of the bcr gene on chromosome 22 and the abl gene on chromosome 9. The bcr-abl fusion gene encodes a novel tyrosine kinase with transforming activity. In this study, we have synthesized a multi-unti ribozyme that targets bcr-abl mRNA. In vitro ribozyme cleavage reactions show increased cleavage efficiency of this multi-unit ribozyme compared with single or double ribozymes. The multiunit ribozyme was then transfected into murine myeloblasts transformed with the bcr-abl gene (32D cells). Ribozyme transfection was accomplished either by liposomes or using follic acid-polylysine as a carrier. Multi-unit ribozyme transfection reduced the level of bcr-abl mRNA 3 logs when transfected via folate receptor-mediated uptake into transformed 32D cells. These results suggest that a multi-unit ribozyme could be an effective therapeutic agent for the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia.

Early treatment decisions with interferon-alfa therapy in early chronic-phase chronic myelogenous leukemia.

1998 ◽  
Vol 16 (3) ◽  
pp. 882-889 ◽  
Author(s):  
S Sacchi ◽  
H M Kantarjian ◽  
T L Smith ◽  
S O'Brien ◽  
S Pierce ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Univariate Analysis ◽  
Group Analysis ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Interferon Alfa ◽  
Myelogenous Leukemia ◽  
Costal Margin ◽  
Hematologic Response

PURPOSE To determine, in patients with Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) on interferon alfa (IFNalpha), whether combining pretreatment characteristics and early response profiles would distinguish patients with differential benefits that would allow better decisions on subsequent therapy. PATIENTS AND METHODS A total of 274 patients treated from 1982 through 1990 with IFNalpha regimens were analyzed. A second group of 137 patients treated with IFNalpha and low-dose cytarabine (ara-C) between 1990 and 1994 was later used to confirm the guidelines derived from the original study group analysis. Patients' pretreatment factors and response to IFNalpha therapy at 3, 6, and 12 months were analyzed in relation to subsequent achievement of major cytogenetic response. After univariate analysis of prognostic factors, a multivariate analysis selected, at 6 months, independent pretreatment factors that added to the response status in predicting subsequent outcome. The results were then applied at the 3- and 12-month periods and confirmed in the subsequent population. RESULTS Response to IFNalpha therapy at 3, 6, and 12 months was a significant predictor of later major cytogenetic response. The presence of splenomegaly > or = 5 cm below the costal margin (BCM) or thrombocytosis > or = 700 x 10(9)/L pretreatment added significant independent prediction to response. At 6 months, patients with a partial hematologic response (PHR) or resistant disease had a less than 10% chance of achieving a later major cytogenetic response, as were those in complete hematologic response (CHR) and who had pretreatment splenomegaly and thrombocytosis. Applying the model at 3 months showed that only patients with < or = PHR and pretreatment splenomegaly or thrombocytosis at 3 months had such a low major cytogenetic response rate. Finally, at 12 months, patients with CHR still had a 15% to 25% chance of having a major cytogenetic response later if they did not have pretreatment splenomegaly and thrombocytosis. CONCLUSION This analysis allows better selection of patients with Ph-positive CML on IFNalpha therapy for continuation of IFNalpha versus changing therapy early in the course of CML. For treatment programs that choose to change patients to other investigational therapies (eg, intensive chemotherapy and/or autologous stem-cell transplantation [SCT]), baseline outcome expectations are provided for patients continued on IFNalpha therapy, against which the results of new approaches can be compared.

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