Systemic mastocytosis with associated myeloproliferative disease and precursor B lymphoblastic leukaemia with t(13;13)(q12;q22) involving<i>FLT3</i>

Tzankov, Alexandar; Sotlar, Karl; Mühlematter, Dominique; Theocharides, Alexandre; Went, Philip; Jotterand, Martine; Horny, Hans‐Peter; Dirnhofer, Stephan

doi:10.1136/jcp.2008.058073

Cited by 28 publications

(21 citation statements)

References 9 publications

(10 reference statements)

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“…An example is lymphoid or biphenotypic (mixed) blast crisis in CML [90][91][92]. In rare cases, subclone formation from LSC may even result in the development of two histologically and cytogenetically unrelated, but still monoclonal neoplasms [92][93][94][95]. It has also been reported that hematopoietic neoplasms even produce a monoclonal microenvironment or a monoclonal microvasculature [96][97][98].…”

Section: Subclone Formation and Plasticity Of Lscmentioning

confidence: 99%

Targeting of Leukemia-Initiating Cells to Develop Curative Drug Therapies: Straightforward but Nontrivial Concept

Valent¹

2011

CCDT

124

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The concept of leukemic stem cells (LSC) is increasingly employed to explain the biology of various myeloid neoplasms and to screen for essential targets, with the hope to improve drug therapy through elimination of disease-initiating cells. Although the stem cell hypothesis may apply to all neoplasms, leukemia-initiating cells have so far only been characterized in some detail in advanced acute (AML) and chronic myeloid leukemia (CML). An intriguing observation is that although expressing various targets, LSC often remain unresponsive against most drugs, presumably because of 'intrinsic' resistance. Moreover, LSC represent heterogeneous populations of cells, grow in separate subclones, and acquire numerous defects, which points to substantial genetic instability and stem cell plasticity. The situation is complicated by the fact that stem cell evolution is a step-wise process with variable latency periods, so that many LSC-derived subclones remain small (undetectable) at diagnosis, but later, during therapy, may expand to a dominant clone and clinically overt relapsing disease. Finally the interaction between LSC and the microenvironment may contribute to stem cell function and LSC resistance. Taking all these considerations into account, the application of broadly acting targeted drugs and of drug combinations has been proposed in order to better suppress or even eliminate LSC in AML and CML. The current article provides a summary of our knowledge on LSC in various myeloid neoplasms with special reference to novel arising treatment concepts.

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Section: Subclone Formation and Plasticity Of Lscmentioning

confidence: 99%

Targeting of Leukemia-Initiating Cells to Develop Curative Drug Therapies: Straightforward but Nontrivial Concept

Valent¹

2011

CCDT

124

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“…In such cases, the neoplastic mast cells and myeloid cells shared a common clonal origin and both harbored the activating KIT mutation [43]. There are infrequent reports of mastocytosis with additional lymphocytic neoplasia [44,45]. However, the activating KIT mutation was usually not detected in cells of the accompanying lymphocytic disease [44].…”

Section: Discussionmentioning

confidence: 99%

Constitutive Kit activity triggers B-cell acute lymphoblastic leukemia-like disease in mice

Weidemann

Behrendt

Schoedel

et al. 2017

Experimental Hematology

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Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and is of pro-or pre-B cell origin in most cases. The receptor tyrosine kinase KIT is expressed by hematopoietic stem and precursor cells. Gain-of-function mutations of KIT cause systemic mastocytosis, which is characterized by abnormal accumulations of mast cells. We previously reported a mouse model of mastocytosis based on conditional expression of a constitutively active Kit protein. Half of these animals developed leukemic disease of B lineage origin. Herein, we report that this condition bears striking similarities to human B-ALL. The immuno-phenotype of the leukemic cells was compatible with a pro-B cell origin, as was the finding of immunoglobulin heavy chain gene rearrangements in all cases, whereas light chain loci were mostly not rearranged. Leukemogenesis was independent of pre-B cell receptor expression.Primary leukemic cells and permanent cell lines derived from these were serially transplantable and rapidly killed the recipients. In few animals, the leukemia was of T cell origin with abnormal CD4/8 double positive T cell precursors dominating in the circulation. In summary, we report a novel ALL mouse model that may prove useful for in vivo drug testing and identification of novel oncogenic mutations and principles.

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“…Review of the current literature shows that AHNMD primarily consists of myeloid malignancies—particularly acute myeloid leukaemia, chronic myelomonocytic leukaemia and chronic myelogenous leukaemia 5. There are rare reports of lymphoid neoplasms, including plasma cell dyscrasia,6 chronic lymphocytic leukaemia7 and B-lymphoblastic leukaemia,8 associated with SM. We now add to this list the rare occurrence of KIT D816V+ acute erythroid leukaemia (erythroid/myeloid type) as the AHNMD.…”

Section: Discussionmentioning

confidence: 99%

KIT^D816V+systemic mastocytosis associated with KIT^D816V+acute erythroid leukaemia: first case report with molecular evidence for same progenitor cell derivation

Sotlar

et al. 2009

J Clin Pathol

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A case of systemic mastocytosis associated with a clonal haematological non-mast cell lineage disease (SM-AHNMD), where the associated disease is acute erythroid leukaemia (erythroid/myeloid type), is reported. Interestingly, molecular studies showed the KIT D816V+ mutation not only in the mast cells, but also in the myeloid blast population and the leukaemic erythroid cells. As is the case with most erythroid leukaemias, the patient had a very aggressive clinical course and died shortly after diagnosis. It is believed that this is the first reported case of systemic mastocytosis with erythroid leukaemia where the KIT D816V+ mutation was detected in all three cell types. Molecular findings provide evidence for derivation of these seemingly morphologically distinct lesions from the same clonal precursor cell. From a practice standpoint, this case illustrates the importance of definitively diagnosing the associated non-mast cell lineage disease due to its prognostic implications.A previously healthy, adult individual, in the sixth decade of life, who had no significant past medical or surgical history, presented with fatigue. The only medication was a daily 61 mg aspirin.A complete blood count revealed pancytopenia with rare myeloblasts identified (,1%). Overt dysplasia or circulating mast cells were not identified. Bone marrow aspirate smears showed marked erythroid predominance with increased immature precursors and dysplastic features characterised by circumferential cytoplasmic vacuolisation, nuclear contour irregularities and multilobation ( fig 1A,B). Myeloblasts were increased, some smaller in size, with scant cytoplasm and minimal granulation (fig 1A,B). Mast cells were quite conspicuous and exhibited atypical spindled morphology (fig 1A,B). Megakaryocytes were decreased; rare small, dysplastic, hypolobated forms were seen.A 500-cell differential count showed 69% erythroid precursors, 18% myeloblasts and 13% other (granulocytic precursors, lymphocytes, eosinophils). The bone marrow core biopsy was hypercellular, with abnormally thickened bony trabeculae and paratrabecular compact aggregates of spindled cells (fig 1C,D). The remaining marrow showed expanded groups of blastic mononuclear cells, many with pronormoblast cytology (round nuclei with multiple, elongated nucleoli), often associated with more mature appearing red cell precursors.Immunohistochemistry for tryptase highlighted paratrabecular mast cell aggregates with atypical spindled morphology and increased interstitial mast cells (fig 1F). The mast cells showed aberrant CD25 positivity (data not shown). CD117 showed two patterns of staining intensity: strong positivity in the mast cells, and weaker positivity in the groups of pronormoblasts and scattered myeloblasts ( fig 1E). CD34 showed increased blasts (,10-15%), and haemoglobin A showed the clusters of immature normoblasts. The presence of increased and spindled mast cells forming compact dense aggregates with aberrant CD25 expression indicated systemic mastocytosis (SM). The non-mast c...

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Systemic mastocytosis with associated myeloproliferative disease and precursor B lymphoblastic leukaemia with t(13;13)(q12;q22) involvingFLT3

Cited by 28 publications

References 9 publications

Targeting of Leukemia-Initiating Cells to Develop Curative Drug Therapies: Straightforward but Nontrivial Concept

Targeting of Leukemia-Initiating Cells to Develop Curative Drug Therapies: Straightforward but Nontrivial Concept

Constitutive Kit activity triggers B-cell acute lymphoblastic leukemia-like disease in mice

KIT^D816V+systemic mastocytosis associated with KIT^D816V+acute erythroid leukaemia: first case report with molecular evidence for same progenitor cell derivation

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Systemic mastocytosis with associated myeloproliferative disease and precursor B lymphoblastic leukaemia with t(13;13)(q12;q22) involvingFLT3

Cited by 28 publications

References 9 publications

Targeting of Leukemia-Initiating Cells to Develop Curative Drug Therapies: Straightforward but Nontrivial Concept

Targeting of Leukemia-Initiating Cells to Develop Curative Drug Therapies: Straightforward but Nontrivial Concept

Constitutive Kit activity triggers B-cell acute lymphoblastic leukemia-like disease in mice

KITD816V+systemic mastocytosis associated with KITD816V+acute erythroid leukaemia: first case report with molecular evidence for same progenitor cell derivation

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KIT^D816V+systemic mastocytosis associated with KIT^D816V+acute erythroid leukaemia: first case report with molecular evidence for same progenitor cell derivation