scholarly journals Lineage Switching in Acute Leukemias: A Consequence of Stem Cell Plasticity?

2012 ◽  
Vol 2012 ◽  
pp. 1-18 ◽  
Author(s):  
Elisa Dorantes-Acosta ◽  
Rosana Pelayo
Keyword(s):  
Cell Fate ◽  
High Efficiency ◽  
Current Knowledge ◽  
Lymphoblastic Leukemia ◽  
Survival Rates ◽  
Cell Lineage ◽  
Leukemic Cells ◽  
Acute Leukemias ◽  
Cell Fate Decisions ◽  
Lineage Switch

Acute leukemias are the most common cancer in childhood and characterized by the uncontrolled production of hematopoietic precursor cells of the lymphoid or myeloid series within the bone marrow. Even when a relatively high efficiency of therapeutic agents has increased the overall survival rates in the last years, factors such as cell lineage switching and the rise of mixed lineages at relapses often change the prognosis of the illness. During lineage switching, conversions from lymphoblastic leukemia to myeloid leukemia, or vice versa, are recorded. The central mechanisms involved in these phenomena remain undefined, but recent studies suggest that lineage commitment of plastic hematopoietic progenitors may be multidirectional and reversible upon specific signals provided by both intrinsic and environmental cues. In this paper, we focus on the current knowledge about cell heterogeneity and the lineage switch resulting from leukemic cells plasticity. A number of hypothetical mechanisms that may inspire changes in cell fate decisions are highlighted. Understanding the plasticity of leukemia initiating cells might be fundamental to unravel the pathogenesis of lineage switch in acute leukemias and will illuminate the importance of a flexible hematopoietic development.

scholarly journals Vital roles of mTOR complex 2 in Notch-driven thymocyte differentiation and leukemia

2012 ◽  
Vol 209 (4) ◽  
pp. 713-728 ◽  
Author(s):  
Keunwook Lee ◽  
Ki Taek Nam ◽  
Sung Hoon Cho ◽  
Prathyusha Gudapati ◽  
Yoonha Hwang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Notch Signaling ◽  
Cell Fate ◽  
Lymphoblastic Leukemia ◽  
Notch Receptor ◽  
Leukemic Cells ◽  
Cell Fate Decisions ◽  
Proliferation And Differentiation ◽  
Physiological Outcomes

Notch plays critical roles in both cell fate decisions and tumorigenesis. Notch receptor engagement initiates signaling cascades that include a phosphatidylinositol 3-kinase/target of rapamycin (TOR) pathway. Mammalian TOR (mTOR) participates in two distinct biochemical complexes, mTORC1 and mTORC2, and the relationship between mTORC2 and physiological outcomes dependent on Notch signaling is unknown. In this study, we report contributions of mTORC2 to thymic T-cell acute lymphoblastic leukemia (T-ALL) driven by Notch. Conditional deletion of Rictor, an essential component of mTORC2, impaired Notch-driven proliferation and differentiation of pre-T cells. Furthermore, NF-κB activity depended on the integrity of mTORC2 in thymocytes. Active Akt restored NF-κB activation, a normal rate of proliferation, and differentiation of Rictor-deficient pre-T cells. Strikingly, mTORC2 depletion lowered CCR7 expression in thymocytes and leukemic cells, accompanied by decreased tissue invasion and delayed mortality in T-ALL driven by Notch. Collectively, these findings reveal roles for mTORC2 in promoting thymic T cell development and T-ALL and indicate that mTORC2 is crucial for Notch signaling to regulate Akt and NF-κB.

scholarly journals Cell fate clusters in ICM organoids arise from cell fate heredity and division: a modelling approach

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Tim Liebisch ◽  
Armin Drusko ◽  
Biena Mathew ◽  
Ernst H. K. Stelzer ◽  
Sabine C. Fischer ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Division ◽  
Cell Fate ◽  
Inner Cell Mass ◽  
Cell Mass ◽  
Cell Lineage ◽  
Cell Fate Decision ◽  
Cell Fate Decisions ◽  
Chemical Signalling ◽  
Fate Decision

AbstractDuring the mammalian preimplantation phase, cells undergo two subsequent cell fate decisions. During the first decision, the trophectoderm and the inner cell mass are formed. Subsequently, the inner cell mass segregates into the epiblast and the primitive endoderm. Inner cell mass organoids represent an experimental model system, mimicking the second cell fate decision. It has been shown that cells of the same fate tend to cluster stronger than expected for random cell fate decisions. Three major processes are hypothesised to contribute to the cell fate arrangements: (1) chemical signalling; (2) cell sorting; and (3) cell proliferation. In order to quantify the influence of cell proliferation on the observed cell lineage type clustering, we developed an agent-based model accounting for mechanical cell–cell interaction, i.e. adhesion and repulsion, cell division, stochastic cell fate decision and cell fate heredity. The model supports the hypothesis that initial cell fate acquisition is a stochastically driven process, taking place in the early development of inner cell mass organoids. Further, we show that the observed neighbourhood structures can emerge solely due to cell fate heredity during cell division.

scholarly journals Characterization of acute undifferentiated leukemia by combined analysis of plasma membrane-associated gamma-glutamyltranspeptidase and soluble terminal transferase

Blood ◽  
1985 ◽  
Vol 66 (2) ◽  
pp. 255-258 ◽  
Author(s):  
D Heumann ◽  
G Losa ◽  
C Barras ◽  
A Morell ◽  
V von Fliedner
Keyword(s):  
Plasma Membrane ◽  
Acute Lymphoblastic Leukemia ◽  
Enzyme Activities ◽  
Colorimetric Assay ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
Acute Leukemias ◽  
Combined Analysis ◽  
Enzyme Markers

Abstract gamma-Glutamyltranspeptidase (gamma-GT) is a plasma membrane-associated enzyme present in blasts of certain acute leukemias. We analyzed 90 cases of undifferentiated and differentiated acute leukemias for gamma- GT, using a colorimetric assay. Blasts of all patients with common acute lymphoblastic leukemia (ALL) and T-ALL were negative for gamma-GT (less than 5 units). In contrast, gamma-GT was significantly elevated in acute myeloblastic or monoblastic leukemia blasts (P less than .001). In 16 cases of acute undifferentiated leukemia (AUL) studied, the levels of gamma-GT ranged from 0 to 93 units; in eight cases, gamma- GT was positive (greater than 5 units), and six of these had 2% to 5% Sudan black-positive leukemic cells in the blast-enriched suspension. Combined gamma-GT/TdT analysis revealed that both enzyme markers were mutually exclusive in 75% of AUL cases, suggesting that gamma-GT+/TdT- blasts are of nonlymphoid origin, and gamma-GT-/TdT+ blasts are of lymphoid origin. Two cases were devoid of both enzyme activities and could represent truly undifferentiated leukemia. Thus, combined gamma- GT/TdT analysis underlines the heterogeneity of AUL and appears to be useful in defining the lineage commitment of undifferentiated leukemic blasts.

Adoptive T-Cell Therapy for B-Cell Acute Lymphoblastic Leukemia: Preclinical Studies

Blood ◽  
1999 ◽  
Vol 94 (10) ◽  
pp. 3531-3540 ◽  
Author(s):  
Angelo A. Cardoso ◽  
J. Pedro Veiga ◽  
Paolo Ghia ◽  
Hernani M. Afonso ◽  
W. Nicholas Haining ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
Adoptive T Cell Therapy ◽  
Leukemic Cells ◽  
Acute Leukemias ◽  
T Cell Lines

We have previously shown that leukemia-specific cytotoxic T cells (CTL) can be generated from the bone marrow of most patients with B-cell precursor acute leukemias. If these antileukemia CTL are to be used for adoptive immunotherapy, they must have the capability to circulate, migrate through endothelium, home to the bone marrow, and, most importantly, lyse the leukemic cells in a leukemia-permissive bone marrow microenvironment. We demonstrate here that such antileukemia T-cell lines are overwhelmingly CD8+ and exhibit an activated phenotype. Using a transendothelial chemotaxis assay with human endothelial cells, we observed that these T cells can be recruited and transmigrate through vascular and bone marrow endothelium and that these transmigrated cells preserve their capacity to lyse leukemic cells. Additionally, these antileukemia T-cell lines are capable of adhering to autologous stromal cell layers. Finally, autologous antileukemia CTL specifically lyse leukemic cells even in the presence of autologous marrow stroma. Importantly, these antileukemia T-cell lines do not lyse autologous stromal cells. Thus, the capacity to generate anti–leukemia-specific T-cell lines coupled with the present findings that such cells can migrate, adhere, and function in the presence of the marrow microenvironment enable the development of clinical studies of adoptive transfer of antileukemia CTL for the treatment of ALL.

scholarly journals Lineage switch in acute leukemia

Blood ◽  
1984 ◽  
Vol 64 (3) ◽  
pp. 701-706 ◽  
Author(s):  
S Stass ◽  
J Mirro ◽  
S Melvin ◽  
CH Pui ◽  
SB Murphy ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
Childhood Leukemia ◽  
Clonal Selection ◽  
Lymphoblastic Leukemia ◽  
Cell Lineage ◽  
Leukemic Cell ◽  
High Dose ◽  
Drug Induced ◽  
Lineage Switch

Abstract Conversions of leukemic cell lineage (lymphoid or myeloid) have been reported only rarely. Our review of the cytochemical and immunophenotypic features of 89 cases of childhood leukemia in marrow relapse indicated lineage switch (lymphoid to myeloid or the reverse) in six patients (6.7%). Five patients with acute lymphoblastic leukemia (ALL) at diagnosis had converted to acute nonlymphoblastic leukemia (ANLL), and one had converted from ANLL to ALL. Each child received lineage-specific multiagent chemotherapy when initially diagnosed, and all achieved a complete remission. After conversion, four patients readily achieved second remissions with treatment for the phenotype evident at lineage switch. Two patients with ANLL at conversion failed ALL-directed reinduction, while one of the two responded to high-dose cytarabine but died during bone marrow hypoplasia, emphasizing the importance of prompt recognition of lineage switch and selection of an appropriate plan of retreatment. Cytogenetic studies disclosed evidence of clonal selection in one patient and clonal stability in two. These findings indicate an unexpectedly high frequency of lineage switch in patients who relapse in the bone marrow after intensive chemotherapy. Although specific causative factors could not be identified, our observations suggest at least two general mechanisms for lineage switch in acute leukemia. In one, chemotherapy appears to eradicate the dominant clone present at diagnosis, permitting expansion of a secondary clone with a different phenotype. In the second, drug-induced changes in the original clone may either amplify or suppress differentiation programs so that phenotypic shift is possible.

The Reliability and Specificity of c-kit for the Diagnosis of Acute Myeloid Leukemias and Undifferentiated Leukemias

Blood ◽  
1998 ◽  
Vol 92 (2) ◽  
pp. 596-599 ◽  
Author(s):  
M.C. Bene ◽  
M. Bernier ◽  
R.O. Casasnovas ◽  
G. Castoldi ◽  
W. Knapp ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Cell Lineage ◽  
Specific Marker ◽  
Acute Leukemias ◽  
Routine Basis ◽  
Immunological Classification ◽  
B Lineage ◽  
Acute Myeloid

Abstract We document findings on c-kit (CD117) expression in 1,937 pediatric and adult de novo acute leukemia cases, diagnosed in five single European centers. All cases were well characterized as to the morphologic, cytochemical, and immunologic features, according to the European Group for the Immunological Classification of Leukemias (EGIL). The cases included 1,103 acute myeloid leukemia (AML), 819 acute lymphoblastic leukemia (ALL), 11 biphenotypic acute leukemia (BAL), and 4 undifferentiated (AUL). c-kit was expressed in 741 (67%) AML cases, regardless of the French-American-British (FAB) subtype, one third of BAL, all four AUL, but only in 34 (4%) of ALL cases. The minority of c-kit+ ALL cases were classified as: T-cell lineage (two thirds), mainly pro-T–ALL or T-I, and B lineage (one third); cells from 62% of these ALL cases coexpressed other myeloid markers (CD13, CD33, or both). There were no differences in the frequency of c-kit+ AML or ALL cases according to age being similar in the adult and pediatric groups. Our findings demonstrate that c-kit is a reliable and specific marker to detect leukemia cells committed to the myeloid lineage, and therefore should be included in a routine basis for the diagnosis of acute leukemias to demonstrate myeloid commitment of the blasts. c-kit expression should score higher, at least one point, in the system currently applied to the diagnosis of BAL, as its myeloid specificity is greater than CD13 and CD33. Findings in ALL and AUL suggest that c-kit identifies a subgroup of cases, which may correspond to leukemias either arising from early prothymocytes and/or early hematopoietic cells, both able to differentiate to the lymphoid and myeloid pathways.

Molecular and Phenotypic Analysis of Philadelphia Chromosome-Positive Bilineage Leukemia: Possibility of a Lineage Switch from T-Lymphoid Leukemia Progenitor to Myeloid Cells Via PU.1 Expression.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4362-4362
Author(s):  
Kazuhiro Nishii ◽  
Fumihiko Monma ◽  
Felipe Lorenzo ◽  
Naoyuki Katayama ◽  
Hiroshi Shiku
Keyword(s):  
T Cell ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Leukemic Cells ◽  
Nucleotide Sequencing ◽  
Phenotypic Analysis ◽  
Lymphoid Leukemia ◽  
Lineage Switch ◽  
Philadelphia Chromosome Positive

Abstract The occurrence of acute bilineage leukemia is thought to be the malignant transformation of a myeloid or lymphoid leukemic progenitor with the potential to differentiate into the other lineages; however, the mechanisms of this lineage switch are not well understood. Here, we show the extremely rare case of adult Philadelphia chromosome positive acute bilineage leukemia, characterized by T-cell acute lymphoblastic leukemia, CD7+CD5+CD14−, and acute myelomonocytic leukemia, CD7−CD5−CD14+. Chromosome analysis showed 46,XY,del(7)(p11.2),t(9;22)(q34;q11.2) in all metaphase and leukemic cells expressed a minor BCR/ABL chimeric gene. When the CD5+CD14− and CD5−CD14+ cells were sorted, a fusion gene of BCR/ABL and a same clonal rearranged band of a T-cell receptor (TCR) gene were detected in both populations. Nucleotide sequencing of the TCRg gene revealed the clonal rearrangement of the V8-JGT2 complex in both populations. Over-expression of PU.1, which plays a fundamental role in myelomonocyte development was found in the sorted CD34+CD7+ and CD5−CD14+, but not CD5+CD14− cells. These results suggest that leukemic progenitor cells in the T-lineage with del(7),t(9;22) chromosome have the potential to differentiate into myeloid lineage and enforced PU.1 expression may contribute in part of this phenomenon. Studies of bilineage leukemia will be important for the understanding of lineage commitment and switch in hematopoietic cells.

scholarly journals Pannexin 1 influences lineage specification of human iPSCs

2021 ◽  
Author(s):  
Rebecca J. Noort ◽  
Grace A. Christopher ◽  
Jessica L. Esseltine
Keyword(s):  
Cell Fate ◽  
Cell Communication ◽  
Cell Lineage ◽  
The Body ◽  
Human Embryos ◽  
Lineage Specification ◽  
Cell Stage ◽  
Cell Fate Decisions ◽  
Pannexin 1 ◽  
Human Ipscs

AbstractEvery single cell in the body communicates with nearby cells to locally organize activities with their neighbors and dysfunctional cell-cell communication can be detrimental during cell lineage commitment, tissue patterning and organ development. Pannexin channels (PANX1, PANX2, PANX3) facilitate purinergic paracrine signaling through the passage of messenger molecules out of cells. PANX1 is widely expressed throughout the body and has recently been identified in human oocytes as well as 2 and 4-cell stage human embryos. Given its abundance across multiple adult tissues and its expression at the earliest stages of human development, we sought to understand whether PANX1 impacts human induced pluripotent stem cells (iPSCs) or plays a role in cell fate decisions. Western blot, immunofluorescence and flow cytometry reveal that PANX1 is expressed in iPSCs as well as all three germ lineages derived from these cells: ectoderm, endoderm, and mesoderm. PANX1 demonstrates differential glycosylation patterns and subcellular localization across the germ lineages. Using CRISPR-Cas9 gene ablation, we find that loss of PANX1 has no obvious impact on iPSC morphology, survival, or pluripotency gene expression. However, PANX1 knockout iPSCs exhibit apparent lineage specification bias during 2-dimensional and 3-dimensional spontaneous differentiation into the three germ lineages. Indeed, loss of PANX1 significantly decreases the proportion of ectodermal cells within spontaneously differentiated cultures, while endodermal and mesodermal representation is increased in PANX1 knockout cells. Importantly, PANX1 knockout iPSCs are fully capable of differentiating toward each specific lineage when exposed to the appropriate external signaling pressures, suggesting that although PANX1 influences germ lineage specification, it is not essential to this process.Graphical abstract

scholarly journals Disruption of a GATA2, TAL1, ERG regulatory circuit promotes erythroid transition in healthy and leukemic stem cells

Blood ◽  
2021 ◽  
Author(s):  
Julie A I Thoms ◽  
Peter Truong ◽  
Shruthi Subramanian ◽  
Kathy Knezevic ◽  
Gregory Harvey ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Fate ◽  
Prognostic Significance ◽  
Regulatory Elements ◽  
Leukemic Cells ◽  
State Transitions ◽  
Specific Cell ◽  
Hematopoietic Stem ◽  
Cell Fate Decisions ◽  
Gene Regulatory

Changes in gene regulation and expression govern orderly transitions from hematopoietic stem cells to terminally differentiated blood cell types. These transitions are disrupted during leukemic transformation but knowledge of the gene regulatory changes underpinning this process is elusive. We hypothesised that identifying core gene regulatory networks in healthy hematopoietic and leukemic cells could provide insights into network alterations that perturb cell state transitions. A heptad of transcription factors (LYL1, TAL1, LMO2, FLI1, ERG, GATA2, RUNX1) bind key hematopoietic genes in human CD34+ haematopoietic stem and progenitor cells (HSPCs) and have prognostic significance in acute myeloid leukemia (AML). These factors also form a densely interconnected circuit by binding combinatorially at their own, and each other's, regulatory elements. However, their mutual regulation during normal haematopoiesis and in AML cells, and how perturbation of their expression levels influences cell fate decisions remains unclear. Here, we integrated bulk and single cell data and found that the fully connected heptad circuit identified in healthy HSPCs persists with only minor alterations in AML, and that chromatin accessibility at key heptad regulatory elements was predictive of cell identity in both healthy progenitors and in leukemic cells. The heptad factors GATA2, TAL1 and ERG formed an integrated sub-circuit that regulates stem cell to erythroid transition in both healthy and leukemic cells. Components of this triad could be manipulated to facilitate erythroid transition providing a proof of concept that such regulatory circuits could be harnessed to promote specific cell type transitions and overcome dysregulated haematopoiesis.

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