Cell lineage analysis of acute leukemia relapse uncovers the role of replication-rate heterogeneity and microsatellite instability

Blood ◽  
2012 ◽  
Vol 120 (3) ◽  
pp. 603-612 ◽  
Author(s):  
Liran I. Shlush ◽  
Noa Chapal-Ilani ◽  
Rivka Adar ◽  
Neta Pery ◽  
Yosef Maruvka ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Myeloid Leukemia ◽  
Blast Crisis ◽  
Cell Lineage ◽  
Cell Subpopulation ◽  
Lymphoid Leukemia ◽  
High Throughput Method ◽  
Leukemia Relapse ◽  
Almost All ◽  
Lineage Trees

Abstract Human cancers display substantial intratumoral genetic heterogeneity, which facilitates tumor survival under changing microenvironmental conditions. Tumor substructure and its effect on disease progression and relapse are incompletely understood. In the present study, a high-throughput method that uses neutral somatic mutations accumulated in individual cells to reconstruct cell lineage trees was applied to hundreds of cells of human acute leukemia harvested from multiple patients at diagnosis and at relapse. The reconstructed cell lineage trees of patients with acute myeloid leukemia showed that leukemia cells at relapse were shallow (divide rarely) compared with cells at diagnosis and were closely related to their stem cell subpopulation, implying that in these instances relapse might have originated from rarely dividing stem cells. In contrast, among patients with acute lymphoid leukemia, no differences in cell depth were observed between diagnosis and relapse. In one case of chronic myeloid leukemia, at blast crisis, most of the cells at relapse were mismatch-repair deficient. In almost all leukemia cases, > 1 lineage was observed at relapse, indicating that diverse mechanisms can promote relapse in the same patient. In conclusion, diverse relapse mechanisms can be observed by systematic reconstruction of cell lineage trees of patients with leukemia.

scholarly journals Kit ligand/mast cell growth factor-independent differentiation of mast cells in myelodysplasia and chronic myeloid leukemic blast crisis

Blood ◽  
1994 ◽  
Vol 84 (12) ◽  
pp. 4322-4332 ◽  
Author(s):  
P Valent ◽  
E Spanblochl ◽  
HC Bankl ◽  
WR Sperr ◽  
C Marosi ◽  
...  
Keyword(s):  
Mast Cell ◽  
Growth Factor ◽  
Mast Cells ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Blast Crisis ◽  
Cell Lineage ◽  
Kit Ligand ◽  
Mast Cell Growth Factor

Autonomous, factor-independent growth and differentiation of malignant cells in preleukemic and leukemic disease states is a well-recognized phenomenon and is often associated with a poor prognosis. Mast cells are distinct hematopoietic cells and express a unique profile of antigens. Growth and differentiation of normal mast cells is dependent on mast cell growth factor (MGF), the ligand of the c-kit protooncogene product. In this study, we screened for mast cell-lineage involvement in 52 patients suffering from myeloid leukemias, myelodysplastic syndromes (MDS), systemic mastocytosis, or other diseases by probing for mast cell-related molecules (c-kit, tryptase, histamine, and MGF) and by analyzing kit ligand/MGF-independent growth of mast cells in long-term suspension culture. Of the 52 patients tested, 2 patients with refractory anemia with excess of blast cells in transformation and 1 patient suffering from chronic myeloid leukemia blast crisis (CML-BC) were diagnosed as mastocytic disease. These patients were characterized by complex chromosomal abnormalities, splenomegaly, high percentages of circulating metachromatic cells (5% to 25%), high levels of cellular tryptase (> 10 ng/10(5) peripheral blood mononuclear cells/mL) and a tryptase/histamine (ng:ng) ratio greater than 1. The metachromatic cells expressed the mast-cell-related surface antigen c-kit, but not basophil-related antigens (CD11b, CDw17). Furthermore, in these 3 patients, spontaneous, MGF-independent growth of mast cells along with spontaneous synthesis of tryptase was demonstrable in long-term culture. No autocrine production, paracrine production, or overproduction of MGF was found. The spontaneous growth of mast cells could neither be abbrogated by addition of monoclonal antibodies (MoAbs) to c-kit nor by MoAbs against MGF (< 5% inhibition), whereas factor (MGF)-dependent differentiation of mast cells in these patients could be abbrogated by MoAbs to c-kit or MoAbs to MGF (> 70% inhibition, P < .001). In addition, serum MGF levels in these patients were within the normal range and MGF could not be detected in cell-free culture supernatants. All 3 patients showed rapid progression of disease and had a survival time of less than 1 year. In conclusion, we describe a unique form of transformation in MDS and CML-BC characterized by mast cell lineage involvement and factor-independent differentiation of mast cells. This form of leukemic transformation has to be delineated from chronic myeloid leukemia with basophilia or basophil crisis, from primary mast cell leukemia, and from monocytic leukemias and myelodysplastic disorders associated with basophilia.

scholarly journals Simultaneous or sequential expression of lymphoid and myeloid phenotypes in acute leukemia

Blood ◽  
1985 ◽  
Vol 65 (1) ◽  
pp. 142-148 ◽  
Author(s):  
PB Neame ◽  
P Soamboonsrup ◽  
G Browman ◽  
RD Barr ◽  
N Saeed ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Myeloid Leukemia ◽  
Chromosomal Abnormalities ◽  
Lymphoblastic Leukemia ◽  
Differentiation Markers ◽  
Lymphoid Leukemia ◽  
Chromosome Marker ◽  
Fab Classification ◽  
Blast Cells ◽  
French American British

Abstract Acute mixed myeloid-lymphoid leukemia is uncommon. We report four cases in which myeloid and lymphoid cell markers were observed simultaneously or sequentially when 94 patients with acute leukemia were phenotyped according to the French-American-British (FAB) classification system, with cytochemical stains, and with immunologically defined differentiation markers (identified by monoclonal antibodies and antiterminal deoxynucleotidyl transferase [TdT]). In one case, conversion from acute lymphoblastic leukemia to acute myeloid leukemia was noted (FAB L1, TdT+ to FAB M4, Auer rods, TdT-). In another patient, two distinct populations of myeloid and lymphoid blast cells were observed simultaneously (TdT-, LeuM1+/TdT+, LeuM1-). In two additional patients, acute leukemia was characterized by the expression of both lymphoid and myeloid markers on the same cell (TdT+/Leu M1+, B4+/Leu M1+ and greater than or equal to 70% TdT+, T11+, My9+). The Philadelphia (Ph1) chromosome was negative in all cases, though other chromosomal abnormalities were noted in three out of four cases. Malignant transformation of a pluripotential stem cell for both lymphoid and myeloid lineages, with or without the Ph1 chromosome marker, could explain the coexistence of distinct populations of lymphoblasts and myeloblasts in acute leukemia. Acute leukemia with a biphenotypic profile may reflect genome depression accompanying neoplasia.

scholarly journals T cell lineage involvement in lymphoid blast crisis of chronic myeloid leukemia

Blood ◽  
1985 ◽  
Vol 66 (5) ◽  
pp. 1155-1161 ◽  
Author(s):  
M Allouche ◽  
A Bourinbaiar ◽  
V Georgoulias ◽  
R Consolini ◽  
A Salvatore ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Blast Crisis ◽  
Interleukin 2 ◽  
Philadelphia Chromosome ◽  
Cell Lineage ◽  
Virtual Absence ◽  
Hodgkin's Lymphomas

Cytochemical and immunologic analysis of cells obtained from two patients with chronic myeloid leukemia (CML) during blast crisis reveals markers suggestive of an immature lymphoid phenotype. Peripheral blood mononuclear cells from both patients generated spontaneous lymphoblastoid colonies in methylcellulose, a phenomenon observed in T cell acute lymphoblastic leukemias and T cell non- Hodgkin's lymphomas but not in any other type of leukemia. Colonies derived from one patient were composed predominantly of OKT3+ cells (89%), whereas those from the second patient displayed 42% OKT3+ and OKT6+ cells. In the second patient's colonies, each of five mitoses contained the Philadelphia chromosome (Ph1) and two of five displayed the same additional karyotypic abnormalities as the blast crisis cells. Cells obtained from the two patients during remission still gave rise to spontaneous T cell colonies (greater than 85% OKT3+) and Ph1 was detected in 33% and 60% of the metaphases, respectively. However, when colony growth was induced by an interleukin 2-containing conditioned medium, less than 5% of mitoses were Ph1-positive. These data suggest that: (1) the T cell lineage might be involved in CML; (2) a subset of T cells may remain unaffected by the leukemic process, as demonstrated by the virtual absence of Ph1 in induced T cell colonies; and (3) the spontaneous colony assay seems to select for the growth of malignant T cells.

scholarly journals Trisomy 13: a new recurring chromosome abnormality in acute leukemia

Blood ◽  
1990 ◽  
Vol 76 (8) ◽  
pp. 1614-1621 ◽  
Author(s):  
H Dohner ◽  
DC Arthur ◽  
ED Ball ◽  
RE Sobol ◽  
FR Davey ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Chromosome Abnormality ◽  
Cell Receptor ◽  
Trisomy 13 ◽  
Lymphoid Leukemia ◽  
High Incidence ◽  
T Cell Receptor Beta ◽  
Hematopoietic Precursor

Abstract A new recurring chromosome abnormality was identified in 8 of 621 consecutive successfully karyotyped adults with de novo acute leukemia. These eight patients had trisomy 13 as the sole cytogenetic abnormality. On central morphologic review, five cases were classified as subtypes of acute myeloid leukemia, one as acute mixed lymphoid and myeloid leukemia, one as acute lymphoid leukemia, and one as acute undifferentiated leukemia. Blasts of all eight cases expressed one or more myeloid differentiation antigens. Three also expressed T-lineage- associated antigens; however, none of these had rearrangement of the T- cell receptor beta, gamma, or delta genes. Four of six cases tested were TdT positive. All eight patients with trisomy 13 were treated with intensive induction chemotherapy; only three entered a short-lived complete remission. Survival of patients with trisomy 13 ranged from 0.5 to 14.7 months, and was significantly shorter than that of the remaining patients (median 9.5 v 16.2 months, P = .007). We conclude that trisomy 13 is a rare, recurring clonal chromosome abnormality in acute leukemia associated with a poor prognosis. Malignant transformation of an immature hematopoietic precursor cell is suggested by the expression of antigens characteristic of both the myeloid and lymphoid lineage, the high incidence of TdT positivity, and the morphologic heterogeneity in these leukemias.

scholarly journals Chronic myeloid leukemia: physical and functional similarities to acute leukemia

Blood ◽  
1977 ◽  
Vol 49 (6) ◽  
pp. 913-923
Author(s):  
JS Senn ◽  
GB Price
Keyword(s):  
Cell Culture ◽  
Chronic Myeloid Leukemia ◽  
Acute Leukemia ◽  
Myeloid Leukemia ◽  
Blast Crisis ◽  
Terminal Phase ◽  
Stable Phase ◽  
Terminal Event ◽  
Cellular Events ◽  
Forming Methods

Blast crisis, closely resembling acute leukemia, is the usual terminal event in chronic myeloid leukemia. Using physical (“fingerprint”) and cultural (colony-forming) methods, we have demonstrated distinctive patterns in the stable phase of chronic myeloid leukemia and in blast crisis. An unusual fingerprint alteration preceding the onset of the terminal phase is noted, and cell culture perturbation is evident at different stages of the disease. Our findings indicate that the application of these methods to the study of hemopoietic disorders is valid, and suggest that the use of such techniques may allow a better understanding of the complex cellular events occurring in the course of chronic myeloid leukemia.

scholarly journals Abnormalities of the retinoblastoma gene in the pathogenesis of acute leukemia

Blood ◽  
1991 ◽  
Vol 78 (12) ◽  
pp. 3259-3268 ◽  
Author(s):  
HG Ahuja ◽  
PS Jat ◽  
A Foti ◽  
M Bar-Eli ◽  
MJ Cline
Keyword(s):  
Acute Leukemia ◽  
Protein Expression ◽  
Blast Crisis ◽  
Philadelphia Chromosome ◽  
Leukemic Cell ◽  
Monocytic Differentiation ◽  
Lymphoid Leukemia ◽  
Acute Leukemias ◽  
Leukemic Cell Lines ◽  
Rb Gene

Abstract The retinoblastoma-susceptibility (Rb) gene is an antioncogene that is frequently altered in retinoblastomas, sarcomas, and some epithelial tumors. We examined the structure of the Rb gene by Southern blotting in 215 cases of leukemias and lymphomas of diverse phenotype and in 15 leukemic cell lines. In selected cases Rb protein expression was examined with specific monoclonal antibodies. Structural abnormalities of the Rb gene with absent protein expression were frequent in all types of human acute leukemia, but were particularly common (27% incidence) in M4 and M5 myeloid leukemia with monocytic differentiation and in Philadelphia chromosome (Ph1)-positive leukemia of lymphoid phenotype (11% to 29% incidence). Changes in Rb were observed early in the transition to acute leukemia in cases of myelodysplastic syndrome and in the accelerated phase of chronic myelocytic leukemia in transition to blast crisis. In one case, molecular changes in Rb could be correlated with leukemia remission and relapse. We conclude that the Rb antioncogene is commonly involved in the evolution of human acute leukemias, particularly in those of a monocytic phenotype and in lymphoid leukemia in which there is an antecedent alteration of the Ph1 chromosome.

scholarly journals T cell lineage involvement in lymphoid blast crisis of chronic myeloid leukemia

Blood ◽  
1985 ◽  
Vol 66 (5) ◽  
pp. 1155-1161 ◽  
Author(s):  
M Allouche ◽  
A Bourinbaiar ◽  
V Georgoulias ◽  
R Consolini ◽  
A Salvatore ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Blast Crisis ◽  
Interleukin 2 ◽  
Philadelphia Chromosome ◽  
Cell Lineage ◽  
Virtual Absence ◽  
Hodgkin's Lymphomas

Abstract Cytochemical and immunologic analysis of cells obtained from two patients with chronic myeloid leukemia (CML) during blast crisis reveals markers suggestive of an immature lymphoid phenotype. Peripheral blood mononuclear cells from both patients generated spontaneous lymphoblastoid colonies in methylcellulose, a phenomenon observed in T cell acute lymphoblastic leukemias and T cell non- Hodgkin's lymphomas but not in any other type of leukemia. Colonies derived from one patient were composed predominantly of OKT3+ cells (89%), whereas those from the second patient displayed 42% OKT3+ and OKT6+ cells. In the second patient's colonies, each of five mitoses contained the Philadelphia chromosome (Ph1) and two of five displayed the same additional karyotypic abnormalities as the blast crisis cells. Cells obtained from the two patients during remission still gave rise to spontaneous T cell colonies (greater than 85% OKT3+) and Ph1 was detected in 33% and 60% of the metaphases, respectively. However, when colony growth was induced by an interleukin 2-containing conditioned medium, less than 5% of mitoses were Ph1-positive. These data suggest that: (1) the T cell lineage might be involved in CML; (2) a subset of T cells may remain unaffected by the leukemic process, as demonstrated by the virtual absence of Ph1 in induced T cell colonies; and (3) the spontaneous colony assay seems to select for the growth of malignant T cells.

scholarly journals Abnormalities of the retinoblastoma gene in the pathogenesis of acute leukemia

Blood ◽  
1991 ◽  
Vol 78 (12) ◽  
pp. 3259-3268 ◽  
Author(s):  
HG Ahuja ◽  
PS Jat ◽  
A Foti ◽  
M Bar-Eli ◽  
MJ Cline
Keyword(s):  
Acute Leukemia ◽  
Protein Expression ◽  
Blast Crisis ◽  
Philadelphia Chromosome ◽  
Leukemic Cell ◽  
Monocytic Differentiation ◽  
Lymphoid Leukemia ◽  
Acute Leukemias ◽  
Leukemic Cell Lines ◽  
Rb Gene

The retinoblastoma-susceptibility (Rb) gene is an antioncogene that is frequently altered in retinoblastomas, sarcomas, and some epithelial tumors. We examined the structure of the Rb gene by Southern blotting in 215 cases of leukemias and lymphomas of diverse phenotype and in 15 leukemic cell lines. In selected cases Rb protein expression was examined with specific monoclonal antibodies. Structural abnormalities of the Rb gene with absent protein expression were frequent in all types of human acute leukemia, but were particularly common (27% incidence) in M4 and M5 myeloid leukemia with monocytic differentiation and in Philadelphia chromosome (Ph1)-positive leukemia of lymphoid phenotype (11% to 29% incidence). Changes in Rb were observed early in the transition to acute leukemia in cases of myelodysplastic syndrome and in the accelerated phase of chronic myelocytic leukemia in transition to blast crisis. In one case, molecular changes in Rb could be correlated with leukemia remission and relapse. We conclude that the Rb antioncogene is commonly involved in the evolution of human acute leukemias, particularly in those of a monocytic phenotype and in lymphoid leukemia in which there is an antecedent alteration of the Ph1 chromosome.

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