Acute Myeloid Leukemia (AML-M2) with a Novel Translocation t(5;11)(q35;q13) and Normal Expression of Cyclin D1.

Abstract Rearrangements of the long arm of chromosome 11 are commonly associated with acute leukemias, with the breakpoints clustered mainly to the 11q23 region, frequently leading to the rearrangement of the MLL gene. CCND1 (previously PRAD1, BCL1), the gene encoding cyclin D1, is located at 11q13. Overexpression of cyclin D1 represents one of the common genetic alterations in human neoplasia, leading to a change in G1-S transition and uncontrolled cell growth. Here we describe the case of a patient with acute myelogenous leukemia (AML) harboring a chromosomal translocation involving 11q13 and a new partner, chromosome 5. A 30-year-old male presented with dyspnea for one month and peripheral blood counts of: hemoglobin 4.9 g/dL, platelets 62 x 109/L and leukocytes 29.5 x 109/L (with 45% of blasts). Bone marrow examination showed a hypercellular marrow with 82% blasts positive for myeloperoxidase and negative for non-specific esterase. The case was classified as AML M2 according to FAB. Classical cytogenetics and spectral karyotyping (SKY) studies performed by unsynchronized culture of the marrow cells revealed an abnormal clone of 46,XY, t(5;11)(q35;q13)[20]. RT-PCR for the rearrangements MLL/AF9, MLL/AF6, MLL/AF4, MLL/ENL, and MLL/ELL were performed and were negative for all of them. Cyclin D1 overexpression was not detected in bone marrow cells by Real Time PCR. The patient was submitted to induction chemotherapy with Daunorrubicin and Cytarabine but obtained only partial remission after 2 cycles of chemotherapy (10% of blasts in bone marrow after second induction). He was than submitted to an allogeneic stem cell transplantation (SCT) from his HLA identical sister. On day +30 after SCT he was in complete hematological remission. The classical cytogenetics study after chemotherapy and bone marrow transplantation revealed karyotypes 46,XY[20] and 46,XX[15]/46,XY[15]chi, respectively. The t(5;11)(q35;q13) represents a recurrent abnormality in renal oncocytoma (benign tumors that occur predominantly in the kidney) and leads frequently to cyclin D1 overexpression. Nevertheless, this cromossomal translocation has never been described in AML.

Download Full-text

Association of the translocation (15;17) with malignant proliferation of promyelocytes in acute leukemia and chronic myelogenous leukemia at blastic crisis

Blood ◽

10.1182/blood.v67.2.270.270 ◽

1986 ◽

Vol 67 (2) ◽

pp. 270-274 ◽

Cited By ~ 32

Author(s):

S Misawa ◽

E Lee ◽

CA Schiffer ◽

Z Liu ◽

JR Testa

Keyword(s):

Bone Marrow ◽

Chronic Myelogenous Leukemia ◽

Bone Marrow Cells ◽

Chronic Phase ◽

Myelogenous Leukemia ◽

Blastic Crisis ◽

Cytogenetic Studies ◽

Chromosomal Breakpoints ◽

Variant Translocation ◽

Marrow Cells

Abstract Cytogenetic studies were performed on nine patients with acute promyelocytic leukemia. Every patient had an identical translocation (15;17) or, in one case, a variant three-way rearrangement between chromosomes 7, 15, and 17. Another patient with chronic myelogenous leukemia was examined at the time of blastic crisis when the patient's bone marrow was infiltrated by hypergranular promyelocytes and blasts. Bone marrow cells contained a t(15;17) as well as a Ph1 chromosome. Only the latter abnormality was observed in the chronic phase of the disease. The translocation (15;17) was detected in all ten patients when bone marrow or peripheral blood cells were cultured for 24 hours prior to making chromosome preparations. However, the t(15;17) was not seen in three of these same cases when bone marrow cells were processed directly. These findings indicate that the t(15;17) is closely associated with acute proliferation of leukemic promyelocytes and that detection of this karyotypic defect may be influenced by the particular cytogenetic processing method used in different laboratories. An analysis of the banding pattern in the variant translocation provided additional evidence favoring chromosomal breakpoints at or very near the junction between bands 17q12 and 17q21 and at 15q22.

Download Full-text

In vitro restoration of polyclonal hematopoiesis in a chronic myelogenous leukemia after in vitro treatment with 4- hydroperoxycyclophosphamide

Blood ◽

10.1182/blood.v65.3.753.bloodjournal653753 ◽

1985 ◽

Vol 65 (3) ◽

pp. 753-757 ◽

Cited By ~ 1

Author(s):

G Degliantoni ◽

L Mangoni ◽

V Rizzoli

Keyword(s):

Bone Marrow ◽

Chronic Myelogenous Leukemia ◽

Early Phase ◽

Bone Marrow Cells ◽

Type A ◽

G6pd Activity ◽

Myelogenous Leukemia ◽

Stem Cell Population ◽

Marrow Cells

Bone marrow cells of a 45-year-old female with Philadelphia chromosome (Ph1)-positive, early-phase chronic myelogenous leukemia (CML), who was heterozygous for the glucose-6-phosphate dehydrogenase (G6PD) locus, were pretreated in vitro with 4-hydroperoxycyclophosphamide (4-HC) and tested for G6PD activity in several colony formation assays and for karyotypic abnormalities. All cells within the mixed (CFU-GEMM), the erythroid burst (BFU-E), and the granulocyte-macrophage (CFU-GM) colonies expressed type A and type B G6PD activity and a normal karyotype, whereas untreated cells expressed type A G6PD and the Ph1 chromosome. This reversal of G6PD activity type and the disappearance of the Ph1 chromosome in colonies grown from 4-HC-treated cells indicate that this cytotoxic agent spares a residual normal stem cell population in bone marrow cells of early-phase CML patients. This finding, in turn, suggests a therapeutic approach in CML based on in vitro chemotherapy of autologous bone marrow grafts.

Download Full-text

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

Blood ◽

10.1182/blood.v73.6.1735.1735 ◽

1989 ◽

Vol 73 (6) ◽

pp. 1735-1741 ◽

Cited By ~ 44

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.

Download Full-text

Gene Rearrangements in Bone Marrow Cells of Patients with Acute Myelogenous Leukemia

Acta Haematologica ◽

10.1159/000041035 ◽

2000 ◽

Vol 103 (3) ◽

pp. 125-134 ◽

Cited By ~ 14

Author(s):

H.M. Schmetzer ◽

S. Braun ◽

D. Wiesner ◽

T. Duell ◽

H.H. Gerhartz ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myelogenous Leukemia ◽

Bone Marrow Cells ◽

Myelogenous Leukemia ◽

Gene Rearrangements ◽

Acute Myelogenous ◽

Marrow Cells

Download Full-text

Characterization of Thy-1 (CDw90) expression in CD34+ acute leukemia

Blood ◽

10.1182/blood.v86.1.60.bloodjournal86160 ◽

1995 ◽

Vol 86 (1) ◽

pp. 60-65 ◽

Cited By ~ 14

Author(s):

JT Holden ◽

RB Geller ◽

DC Farhi ◽

HK Holland ◽

LL Stempora ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Stem Cell ◽

Acute Leukemia ◽

Lymphoblastic Leukemia ◽

Blast Crisis ◽

Myelogenous Leukemia ◽

Acute Leukemias ◽

Hematopoietic Stem

Thy-1 (CDw90) is a phosphatidylinositol-anchored cell surface molecule which, when coexpressed with CD34 in normal human bone marrow, identifies a population of immature cells that includes putative hematopoietic stem cells. To date, the characterization of Thy-1 expression has been confined largely to normal tissues and cell lines. In this study, we evaluated the frequency and intensity of Thy-1 expression as defined by reactivity with the anti-Thy-1 antibody 5E10 in 38 cases of CD34+ acute leukemia (21 acute myelogenous leukemia [AML], 8 chronic myelogenous leukemia [CML] in blast crisis, and 9 acute lymphoblastic leukemia [ALL]). In 34 of 38 cases (89%) the CD34+ cells lacked expression of the Thy-1 antigen. High-density Thy-1 expression was found in 1 case of CML in lymphoid blast crisis, and low- density Thy-1 expression was identified on a portion of the leukemic cells in 2 cases of AML with myelodysplastic features, and 1 case of CML in myeloid blast crisis, suggesting a possible correlation between Thy-1 expression and certain instances of stem cell disorders such as CML and AML with dysplastic features. In contrast, the dissociation of Thy-1 and CD34 expression in the majority of acute leukemias studied suggests that the development of these leukemias occurs at a later stage than the hematopoietic stem cell. Characterization of Thy-1 expression in acute leukemia may eventually provide insights into the origin of the disease. In addition, separation of leukemic blasts from normal stem cells based on Thy-1 expression may prove useful in assessing residual disease, as well as in excluding leukemic blasts from stem cell preparations destined for autologous bone marrow or peripheral stem cell transplantation.

Download Full-text

The Production of Vascular Endothelial Growth Factor Is Decreased in Acute Myelogenous Leukemia Cases That Are Treated with Chemotherapeutic Agents and Show the Prolonged Bone Marrow Suppression.

Blood ◽

10.1182/blood.v110.11.4313.4313 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4313-4313

Author(s):

Haruko Tashiro ◽

Mitsuho Noguchi ◽

Ryosuke Shirasaki ◽

Kazuo Kawasugi ◽

Naoki Shirafuji

Keyword(s):

Bone Marrow ◽

Vascular Endothelial Growth Factor ◽

Bone Marrow Cells ◽

Bone Marrow Suppression ◽

Myelogenous Leukemia ◽

Vegf Receptor ◽

Vascular Endothelial ◽

Acute Myelogenous ◽

Endothelial Growth Factor ◽

Marrow Cells

Abstract Objective: There have been reported that the levels of serum vascular endothelial growth factor (VEGF) were decreased in aplastic anemia cases. We investigated VEGF system after chemotherapy to acute myelogenous leukemia (AML) cases, and determined whether VEGF system influenced the prolonged bone marrow suppression in these cases. Materials and Methods: Sera and bone marrow cells were prepared from 30 AML cases including 10 cases of AML (M3) at the onset of the disease, after chemotherapy, and the recovery periods, and the concentration of VEGF in sera of the patients and in the conditioned media obtained from bone marrow-cell cultures was measured with ELISA kit (Quantikine; R&D Systems). The expression of VEGF, VEGF receptor type-1 and VEGF receptor type-2 was analyzed with RT-PCR. The biological effect of VEGF on the bone marrow cells which showed the prolonged suppression after chemotherapy was assayed with colony-formation with or without any cytokines. Result and Discussion: As was reported previously, VEGF levels were significantly increased in M3 cases. In other types of AML cases the levels of VEGF production varied. When patients were given chemotherapy and the bone marrow suppression was prolonged, the production levels of VEGF were significantly diminished less than that observed in AML cases with normal bone marrow recovery. In M3 cases that were treated with all-trans retinoic acid and the prolonged bone marrow-suppression was observed, VEGF production was also suppressed. The expression of VEGFR-1 and -2 was observed in bone marrow cells from prolonged bone marrow suppression cases. In these cases, when bone marrow cells were cultured with VEGF, synergistic effects with G-CSF and EPO were observed with colony-formation assay. These observations indicate that VEGF works on the important role for the hematopoietic recovery after chemotherapy in AML cases.

Download Full-text

New Variant Translocation (8;20)(q22;q13) in Bone Marrow Cells of Extramedullary Blast Crisis in Chronic Myelogenous Leukemia

Cancer Genetics and Cytogenetics ◽

10.1016/s0165-4608(99)00180-6 ◽

2000 ◽

Vol 117 (2) ◽

pp. 167-168 ◽

Cited By ~ 4

Author(s):

Y Harada ◽

K Ishi ◽

T Shirota ◽

T Hayashi

Keyword(s):

Bone Marrow ◽

Chronic Myelogenous Leukemia ◽

Bone Marrow Cells ◽

Blast Crisis ◽

Myelogenous Leukemia ◽

New Variant ◽

Extramedullary Blast Crisis ◽

Variant Translocation ◽

Marrow Cells

Download Full-text

Efficient and Rapid Induction of a Chronic Myelogenous Leukemia-Like Myeloproliferative Disease in Mice Receiving P210 bcr/abl-Transduced Bone Marrow

Blood ◽

10.1182/blood.v92.10.3780.422k15_3780_3792 ◽

1998 ◽

Vol 92 (10) ◽

pp. 3780-3792 ◽

Cited By ~ 38

Author(s):

Warren S. Pear ◽

Juli P. Miller ◽

Lanwei Xu ◽

John C. Pui ◽

Benny Soffer ◽

...

Keyword(s):

Bone Marrow ◽

Chronic Myelogenous Leukemia ◽

Fluorescent Protein ◽

Bone Marrow Cells ◽

Blast Crisis ◽

Extramedullary Hematopoiesis ◽

Myelogenous Leukemia ◽

Myeloproliferative Disease ◽

Cell Counts ◽

Marrow Cells

Expression of the 210-kD bcr/abl fusion oncoprotein can cause a chronic myelogenous leukemia (CML)-like disease in mice receiving bone marrow cells transduced by bcr/abl-encoding retroviruses. However, previous methods failed to yield this disease at a frequency sufficient enough to allow for its use in the study of CML pathogenesis. To overcome this limitation, we have developed an efficient and reproducible method for inducing a CML-like disease in mice receiving P210 bcr/abl-transduced bone marrow cells. All mice receiving P210 bcr/abl-transduced bone marrow cells succumb to a myeloproliferative disease between 3 and 5 weeks after bone marrow transplantation. The myeloproliferative disease recapitulates many of the hallmarks of human CML and is characterized by high white blood cell counts and extensive extramedullary hematopoiesis in the spleen, liver, bone marrow, and lungs. Use of a retroviral vector coexpressing P210 bcr/abl and green fluorescent protein shows that the vast majority of bcr/abl-expressing cells are myeloid. Analysis of the proviral integration pattern shows that, in some mice, the myeloproliferative disease is clonal. In multiple mice, the CML-like disease has been transplantable, inducing a similar myeloproliferative syndrome within 1 month of transfer to sublethally irradiated syngeneic recipients. The disease in many of these mice has progressed to the development of acute lymphoma/leukemia resembling blast crisis. These results demonstrate that murine CML recapitulates important features of human CML. As such, it should be an excellent model for addressing specific issues relating to the pathogenesis and treatment of this disease.

Download Full-text

AML1-ETO Collaborates with the Homeobox Gene Meis1 in Inducing Acute Leukemia in the Mouse Bone Marrow Transplantation Model.

Blood ◽

10.1182/blood.v112.11.928.928 ◽

2008 ◽

Vol 112 (11) ◽

pp. 928-928 ◽

Cited By ~ 3

Author(s):

Vegi M. Naidu ◽

Vijay P.S. Rawat ◽

Christina Schessl ◽

Konstantin Petropoulus ◽

Monica Cusan ◽

...

Keyword(s):

Bone Marrow ◽

Acute Leukemia ◽

Insertional Mutagenesis ◽

Fusion Gene ◽

Genetic Alterations ◽

Control Group ◽

Mouse Bone Marrow ◽

Acute Leukemias ◽

Hox Gene ◽

Blast Cells

Abstract AML1-ETO is the most frequent fusion gene in human AML. Previously, we and others have demonstrated that the fusion is not able to cause leukaemia on its own in experimental murine models, but that it needs collaborative partners. However, although mutations such as the FLT3-length mutation and C-KIT mutations were defined as important collaborative genetic events in AML1-ETO positive AML, most human AML1-ETO cases do not carry these mutations, indicating the presence of unkown collaborative partners in these patients. On the other hand Meis1, a HOX gene co-factor, belonging to the TALE family of homeodomain proteins, has a well established function as a protooncogene with a strong collaborative potential in Hox gene associated AML in mice. First we confirmed expression of MEIS1 in some patients with AML1-ETO positive AML by real-time PCR. Based on this we sought to determine if AML1-ETO can collaborate with Meis1 in inducing acute leukemias: single constructs or both genes were co-transfected in 5-FU treated primary murine bone marrow cells by retroviral gene transfer, using MSCV retroviral constructs with an IRES–GFP or YFP cassette. Mice were transplanted with BM cells expressing Meis1 alone (n=10), with BM cells solely expressing the fusion gene (n=10) or EGFP (n=7, control) or with BM expressing both genetic alterations (n=14). None of the mice in the Meis1 and AML1-ETO as well as in the control group developed disease. In contrast, 14 mice transplanted with BM co-expressing AML1-ETO and Meis1 developed lethal disease after a median latency of 102 days. Three mice succumbed to a myeloproliferative syndrome and nine mice died by acute leukemia (6 mice developed AML, 3 mice ALL), which was serially transplantable into secondary recipients (median = 57 days). Immunohistochemistry of various organs of leukemic mice showed massive infiltration with blast cells. In MPS and AML 85 ± 9.3 % of the blast cells co-expressed Gr-1+ and Mac1+. In ALL cases 40 ± 19.9 % of the malignant cells co-expressed Mac1 and the lymphoid-associated B220 antigen. Analysis of retroviral integration did not reveal recurrent integration sites as an indication for insertional mutagenesis. In summary, our data demonstrate for the first time that AML1-ETO can collaborate with Meis1 and identify a novel collaborative partner in t(8;21) positive AML. Furthermore, our analyses demonstrate that Meis1 can collaborate with non-homeobox genes in inducing acute leukemia.

Download Full-text