Ring chromosome 8 and translocation t(8;21) in a patient with acute myeloblastic leukemia

Recurrent translocation t(8;21)(q22;q22) acute myeloid leukemia (AML) is often associated with secondary chromosome changes of which the clinical significance is not clear since they do not seem to impair the prognosis. Uncommon chromosome changes may lead to the identification of leukemogenetic factors associated with t(8;21) since the AML1/RUNX1-ETO fusion gene resulting from the translocation is thought to be unable alone to induce leukemia. We here report a patient with AML, t(8;21) and ring chromosome 8 resulting in partial chromosome 8 deletion. Another patient with partial 8q deletion has been previously reported. It is suggested that more attention be paid to the genes located in distal 8q in relation to leukemogenesis.     

A new translocation t(1;4;11) in congenital acute nonlymphocytic leukemia (acute myeloblastic leukemia)

Summary A new translocation t(1;11;4)(1pter1p32::11q23 11q13::4p164qter) was found in the peripheral blood of a patient with congenital acute myeloblastic leukemia (AML). It was concluted that this translocation may represent a new mutation, which caused the leukemia with very high leukocytosis, hepatosplenomegaly, leukemic infiltration of the majority of the organs, and a very poor prognosis.     

Systemic mastocytosis associated with t(8;21)(q22;q22) acute myeloid leukemia

Although KIT mutations are present in 20–25% of cases of t(8;21)(q22;q22) acute myeloid leukemia (AML), concurrent development of systemic mastocytosis (SM) is exceedingly rare. We examined the clinicopathologic features of SM associated with t(8;21)(q22;q22) AML in ten patients (six from our institutions and four from published literature) with t(8;21) AML and SM. In the majority of these cases, a definitive diagnosis of SM was made after chemotherapy, when the mast cell infiltrates were prominent. Deletion 9q was an additional cytogenetic abnormality in four cases. Four of the ten patients failed to achieve remission after standard chemotherapy and seven of the ten patients have died of AML. In the two patients who achieved durable remission after allogeneic hematopoietic stem cell transplant, recipient-derived neoplastic bone marrow mast cells persisted despite leukemic remission. SM associated with t(8;21) AML carries a dismal prognosis; therefore, detection of concurrent SM at diagnosis of t(8;21) AML has important prognostic implications.     

The ETS genes on chromosome 21 are distal to the breakpoint of the acute myelogenous leukemia translocation (8;21)

The definition of the genetic linkage map of human chromosomes may be helpful in the analysis of cancer-specific chromosome abnormalities. In the translocation (8;21)(q22;q22), a nonrandom cytogenetic abnormality of acute myelogenous leukemia (AML), we previously observed the transposition of the ETS2 gene located at the 21q22 region from chromosome 21 to chromosome 8. However, no ETS2 rearrangements were detected in the DNA of t(8;21)-positive AML cells. Genetic linkage analysis has allowed us to locate the ETS2 gene relative to other loci and to establish that the breakpoint is at an approximate genetic distance of 17 cM from ETS2. When the information from the linkage map is combined with that from molecular studies, it is apparent that (a) the t(8;21) breakpoint does not affect the ETS2 gene structure or the structure of the other four loci proximal to ETS2: D21S55, D21S57, D21S17, and ERG, and ETS-related gene; and (b) the actual DNA sequence involved in the t(8;21) must reside in a 3-cM genetic region between the D21S58 and the D21S55/D21S57 loci, and remains to be identified.     

Localization of human c-mos to chromosome band 8q11 in leukemic cells with the t(8;21) (q22;q22)

Summary Chromosome in situ hybridization studies locate c-mos to chromosome band 8q11 in leukemic cells carrying the t(8;21) (q22;q22). This amends the previous assignment of c-mos to chromosome band 8q22 and conforms with its recent assignment to 8q11 in normal cells and in a cell line with a structurally abnormal chromosome 8. C-mos lies proximally to, and distant from, the breakpoint at 8q22 in the t(8;21) and is unlikely to have a role in the onset of acute myeloid leukemia characterized by this translocation.     

Partial trisomy of chromosome 21 by maternal translocation t(15;21) (q26.2; q21)]

A balanced reciprocal translocation, t(15;21) (q262;q21) was observed in the mother and maternal grandfather of two patients. The propositus, who received the abnormal chromosome 15 from his mother, is trisomic for the distal part of chromosome 21, and his phenotype is that of classical trisomy 21. His sister, who is trisomic for the proximal part of 21q, is slightly retarded but developmentally normal otherwise.     

Network analysis of reverse phase protein expression data: characterizing protein signatures in acute myeloid leukemia cytogenetic categories t(8;21) and inv(16)

Acute myeloid leukemia (AML) patients present with cancerous cells originating from bone marrow. Proteomic data on AML patient cells provides critical information on the key molecules associated with the disease. Here, we introduce a new computational approach to identify complex patterns in protein signaling from reverse phase protein array data. We analyzed the expression of 203 proteins in cells taken from AML patients. Dominant overlapping protein networks between subtypes of AML patients were characterized computationally, through a paired t-test approach looking at relative protein expression. In the first application of this method, we compared recurrent cytogenetic abnormalities inv(16) and t(8;21), both affecting core-binding factor (CBFβ), to normal CD34(+) cells and to each other. Six hundred seventy-eight sets of proteins were identified as significantly different in both inv(16) and t(8;21) compared to controls, at the Bonferroni number, α < 2.44 × 10(-6) . We strengthened our predictions by comparing results to those obtained using lasso regression analysis. Signaling networks were constructed from the protein pairs that were significantly different in the t-test and lasso regression analysis. Predicted networks were also compared to known networks from public protein-protein interaction and signaling databases. By characterizing unique "protein signatures" through this rapid computational analysis, and placing them in the context of canonical biological networks, we identify signaling pathways distinct to subcategories of AML patients.     

A case of acute myeloid leukemia-M2 with trisomy 4 in addition to t(8;21)

t(8;21)(q22;q22) is the most frequently observed karyotypic abnormality associated with acute myeloid leukemia (AML), specifically in FAB-M2. Short-term unstimulated bone marrow (BM) and peripheral blood lymphocyte culture showed 47,XX, +4,t(8;21) in all metaphase plates; and interphase and metaphase results of AML-ETO fusion was positive and trisomy of 4 was confirmed with WCP probes. Trisomy 4 in AML with t(8;21) is a rare numerical abnormality. Here we present such case of patient which may constitute a distinctive subtype.     

Cell-mediated immunity in human acute myeloblastic leukemia

Summary Lymphocyte stimulation tests with autologous myeloblasts were performed in 31 patients with nonlymphatic acute leukemia. Twenty-five patients were receiving chemotherapy combined with immunotherapy; six received chemotherapy only. Thirteen nonleukemic patients with various disorders and six healthy control patients were also studied.It was found that 4/15 patients in 9/38 tests had autologous lymphocytes stimulated by autologous circulating myeloblasts. Bone marrow cells also effected stimulation, significantly more often if the marrow was taken in relapse than when it was taken in remission.However, so-called immunotherapy with allogeneic leukemic myeloblasts and BCG could not be shown to increase these frequencies. Nor did it significantly increase the degree of stimulation measured as DNA synthesis in lymphocytes.Moreover, nonleukemic bone marrow cells from patients with other disorders also stimulated autologous lymphocytes in 1/13 patients. No recognition of autologous myeloblasts was observed when the responding lymphocytes were taken in incomplete remission or during the month preceding relapse.with the technical assistance of T. Lehtinen and A. M. SjögrenSupported by the Swedish Cancer Research Foundation Grant no. 699-B76-04XA     

Efficacy of a combination therapy targeting CDK4/6 and autophagy in a mouse xenograft model of t(8;21) acute myeloid leukemia

One of the most frequent cytogenetic abnormalities in acute myeloid leukemia (AML) is t(8;21). Although patients with t(8;21) AML have a more favorable prognosis than other cytogenetic subgroups, relapse is still common and novel therapeutic approaches are needed. A recent study showed that t(8;21) AML is characterized by CCND2 deregulation and that co-inhibition of CDK4/6 and autophagy induces apoptosis in t(8;21) AML cells. In this study, we examined the in vivo effects of co-inhibiting CDK4/6 and autophagy. We used a mouse model in which t(8;21)-positive Kasumi-1 cells were subcutaneously inoculated into NOD/Shi-scid IL2Rg^null mice. The mice were treated with the autophagy inhibitor chloroquine (CQ), a CDK4/6 inhibitor (either abemaciclib or palbociclib), or a CDK4/6 inhibitor plus CQ. After 20 days of treatment, tumor volume was measured, and immunostaining and transmission electron microscopy observations were performed. There was no change in tumor growth in CQ-treated mice. However, mice treated with a CDK4/6 inhibitor plus CQ had significantly less tumor growth than mice treated with a CDK4/6 inhibitor alone. CDK4/6 inhibitor treatment increased the formation of autophagosomes. The number of single-strand DNA-positive (apoptotic) cells was significantly higher in the tumors of mice treated with a CDK4/6 inhibitor plus CQ than in mice treated with either CQ or a CDK4/6 inhibitor. These results show that CDK4/6 inhibition induces autophagy, and that co-inhibition of CDK4/6 and autophagy induces apoptosis in t(8;21) AML cells in vivo. The results suggest that inhibiting CDK4/6 and autophagy could be a novel and promising therapeutic strategy in t(8;21) AML.     

A novel chromosomal abnormality t (9;14)(p24;q13) in B-acute lymphoblastic leukemia

Acute lymphoblastic leukemia is a malignant disease of the bone marrow in which early lymphoid precursors proliferate and replace the normal hematopoietic cells of the marrow. We describe the clinical, morphologic, immunophenotypic and cytogenetic findings in the case of a 26-year-old man with B-lymphoblastic leukemia. Surface marker analysis revealed that they are positive for CD markers CD10, CD19, CD13, CD34, CD45 and HLA-DR, but negative for CD20, CD33, CD117 and CD11C markers. Cytogenetic analysis established a novel translocation, t (9;14)(p24;q13). Apart from this, spectral karyotyping revealed an additional translocation, t (6p; 14q). This is the first documented case of B-lymphoblastic leukemia with concurrent occurrence of both abnormalities. Further studies are needed to understand the role of this abnormality in carcinogenesis.     

Immunotherapy for remission maintenance in acute myeloblastic leukemia

Summary Forty-eight patients with acute myeloblastic leukemia in remission were treated with immunotherapy in addition to remission-maintenance chemotherapy. The first 16 patients were treated with weekly BCG and a leukemia cell vaccine (group 1). The next 32 patients were randomly allocated to receive BCG and a leukemia cell vaccine given once monthly (group 2) or BCG given monthly with no leukemia cell vaccine (group 3). There was no significant difference in remission duration or survival between the randomly allocated groups (2 and 3).Comparisons with group 1 are limited by the non-random allocation to this group, but selection bias was unlikely and clinical features were similar in the three patient groups. No significant difference in remission duration or survival was seen amongst the three groups studied. There was no advantage in the addition of leukemia cell vaccine (groups 1 and 2) to BCG alone (group 3) and no advantage to weekly (group 1) versus monthly immunotherapy (groups 2 and 3). Only 7 of the 48 patients achieved a second remission, and 4 of these were short-term partial remissions.The following are contributing members of the Toronto Leukemia Study Group: Doctor's Hospital, Harvey Silver MD; Humber Memorial Hospital, Alan Seidenfeld MD; Mississauga Hospital, Michael King MD; Mount Sinai Hospital, Dominic Amato MD; Northwestern Hospital, Wilhelm Kwant MD; Oshawa General Hospital, Hak Chiu MD; St Michael's Hospital, Bernadette Garvey MD, Kenneth Butler MD; St Joseph's Hospital, H. James Watt MD, Murray Davidson MD; Toronto General Hospital, Gerald Scott MD, William Francombe MD, Kenneth Shumak MD; John Crookston MD, PhD; Toronto Western Hospital, James G. Watt MD, David Sutton MD; Michael Baker MD; Domenic Pantalony MD; Wellesley Hospital, Dale Dotten MD; Women's College Hospital, George Kutas MD; York Finch Hospital, Sam Berger MD     

Improvements in survival of adults diagnosed with acute myeloblastic leukemia in the early 21st century

CD200 has been associated with a poor prognosis in acute myeloid leukemia (AML). However, the outcome for AML remains heterogeneous and relies more heavily on treatment procedures received by patients. This study aimed to evaluate the correlations between CD200 expression and its prognostic significance in AML treated using diverse treatments. 160 AML patients treated using different chemotherapeutic approaches were retrospectively reviewed from 2018 to 2021, and the effects of CD200 expression on disease outcomes were evaluated. CD200 expressed in 100/160 (62.5%) cases, defined as the CD200-positive (CD200⁺) group, while the remaining cases were identified as the CD200-negative (CD200⁻) group. The CD200⁺ group had a significantly lower probability of complete remission after the first induction chemotherapy, both in univariate (P=0.002) and multivariate (P=0.023) analyses. In the entire population, CD200 expression exerted no significant effect on disease-free survival (DFS) (P=0.837) nor overall survival (OS) (P=0.155). In the subgroup analysis, CD200 negatively affected OS in patients receiving less-intensive treatments (P=0.005) and those receiving chemotherapy alone (P=0.019). In conclusion, CD200 positive indicates a low remission rate and further reduces long-term survival in patients receiving less-intensive approaches and chemotherapy-alone. Intensive chemotherapy and stem cell transplantation may reduce the adverse effects of CD200 expression on AML patients.