Involvement of the B-lymphoid system in chronic myelogenous leukaemia

Martin, Paul J.; Najfeld, Vesna; Hansen, John A.; Penfold, G.; Jacobson, Robert J.; Fialkow, Philip J.

doi:10.1038/287049a0

Cited by 233 publications

(74 citation statements)

References 12 publications

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“…Moreover, both myeloid and lymphoid cells were affected, mirroring a predicted cascade of hematopoietic differentiation. 10 These findings concur with results of conventional cytogenetics, G6PDH enzymatic activity, X-inactivation and detection of the BCR-ABL1 transcript [11][12][13][14] and validate our FISH approach for the assignment of a typical leukemic genetic lesion to different hematopoietic lineages.…”

Section: Discussionsupporting

confidence: 78%

FIP1L1-PDGFRA in chronic eosinophilic leukemia and BCR-ABL1 in chronic myeloid leukemia affect different leukemic cells

et al. 2007

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We investigated genetically affected leukemic cells in FIP1L1-PDGFRA þ chronic eosinophilic leukemia (CEL) and in BCR-ABL1 þ chronic myeloid leukemia (CML), two myeloproliferative disorders responsive to imatinib. Fluorescence in situ hybridization specific for BCR-ABL1 and for FIP1L1-PDGFRA was combined with cytomorphology or with lineage-restricted monoclonal antibodies and applied in CML and CEL, respectively. In CEL the amount of FIP1L1-PDGFRA þ cells among CD34 þ and CD133 þ cells, B and T lymphocytes, and megakaryocytes were within normal ranges. Positivity was found in eosinophils, granulo-monocytes and varying percentages of erythrocytes. In vitro assays with imatinib showed reduced survival of peripheral blood mononuclear cells but no reduction in colony-forming unit growth medium (CFU-GM) growth. In CML the BCR-ABL1 fusion gene was detected in CD34 þ /CD133 þ cells, granulo-monocytes, eosinophils, erythrocytes, megakaryocytes and B-lymphocytes. Growth of both peripheral blood mononuclear cells and CFU-GM was inhibited by imatinib. This study provided evidence for marked differences in the leukemic masses which are targeted by imatinib in CEL or CML, as harboring FIP1L1-PDGFRA or BCR-ABL1.

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Section: Discussionsupporting

confidence: 78%

FIP1L1-PDGFRA in chronic eosinophilic leukemia and BCR-ABL1 in chronic myeloid leukemia affect different leukemic cells

et al. 2007

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“…The finding that nine lines were Ph-positive proved that the CML stem cell is capable of differentiating to B lymphocytes. 42 Expression of G6PD types in the remaining 63 lines was significantly skewed toward the type found in the leukemic clone. An additional observation was that eight of 33 lymphoid lines expressing the leukemic G6PD type showed karyotypic abnormalities, whereas all of the 14 type A lines had normal karyotypes.…”

Section: Chronic Myelocytic Leukemiamentioning

confidence: 99%

“…42 These B lymphocytes are able to contribute to antibody diversity. In contrast, in lymphoid blast crisis only a single Ig type was found in the few patients in whom the blast cells expressed Ig.…”

Section: Chronic Myelocytic Leukemiamentioning

confidence: 99%

Clonal development of myeloproliferative disorders: clues to hematopoietic differentiation and multistep pathogenesis of cancer

1998

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In November 1996, word reached the University of Washington that Philip Fialkow and his wife, Helen, had died while trekking in Nepal. Over a 30-year period, Dr Fialkow and his colleagues used the cellular mosaicism resulting from X-chromosome inactivation in females as a marker system to investigate the clonal development of human hematopoietic disorders. This review discusses the impact that these studies have had on our understanding of hematopoietic stem cell relationships and the pathogenesis of human neoplasia in general. To appreciate the special role played by studies on clonality, it is necessary to consider how little was known about the origin of leukemias and myeloproliferative disorders and the limited techniques available for their study in the early to mid 1960s. Dr Fialkow and his coworkers were the first to show that myeloproliferative disorders and acute myelogenous leukemias (AML) are clonal diseases at the time of diagnosis and to elucidate the level of differentiation manifested by the originating cell type. Although the myelodysplastic disorders were found to involve a pluripotent stem cell, heterogeneity was found in the level of stem cell involvement in AML. Evidence was obtained to support a multistep pathogenesis of these diseases as well as a clonal but cytogenetically normal stage in some cases of Ph-positive chronic myelogenous leukemia, AML, acute lymphoblastic leukemia and myelodysplasia.

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“…[1][2][3][4][5] Animal models as well as theoretical considerations on the age-specific incidence of CML in human populations suggest that aberrant BCR-ABL expression alone may be enough to explain the chronic phase of the disease. 1,5,6 The BCR-ABL oncoprotein interacts with many substrates in the leukemic cell, which ultimately leads to the CML phenotype.…”

Section: Introductionmentioning

confidence: 99%

Tyrosine kinase inhibitor therapy can cure chronic myeloid leukemia without hitting leukemic stem cells

Lenaerts¹,

Pacheco²,

Traulsen³

et al. 2009

Haematologica

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BackgroundTyrosine kinase inhibitors, such as imatinib, are not considered curative for chronic myeloid leukemia -regardless of the significant reduction of disease burden during treatment -since they do not affect the leukemic stem cells. However, the stochastic nature of hematopoiesis and recent clinical observations suggest that this view must be revisited. Design and MethodsWe studied the natural history of a large cohort of virtual patients with chronic myeloid leukemia under tyrosine kinase inhibitor therapy using a computational model of hematopoiesis and chronic myeloid leukemia that takes into account stochastic dynamics within the hematopoietic stem and early progenitor cell pool. ResultsWe found that in the overwhelming majority of patients the leukemic stem cell population undergoes extinction before disease diagnosis. Hence leukemic progenitors, susceptible to tyrosine kinase inhibitor attack, are the natural target for chronic myeloid leukemia treatment. Response dynamics predicted by the model closely match data from clinical trials. We further predicted that early diagnosis together with administration of tyrosine kinase inhibitor opens the path to eradication of chronic myeloid leukemia, leading to the wash out of the aberrant progenitor cells, ameliorating the patient's condition while lowering the risk of blast transformation and drug resistance. ConclusionsTyrosine kinase inhibitor therapy can cure chronic myeloid leukemia, although it may have to be prolonged. The depth of response increases with time in the vast majority of patients. These results illustrate the importance of stochastic effects on the dynamics of acquired hematopoietic stem cell disorders and have direct relevance for other hematopoietic stem cell-derived diseases.Key words: chronic myeloid leukemia, tyrosine kinase inhibitors, cure, stochastic dynamics. Citation: Lenaerts T, Pacheco JM, Traulsen

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Involvement of the B-lymphoid system in chronic myelogenous leukaemia

Cited by 233 publications

References 12 publications

FIP1L1-PDGFRA in chronic eosinophilic leukemia and BCR-ABL1 in chronic myeloid leukemia affect different leukemic cells

FIP1L1-PDGFRA in chronic eosinophilic leukemia and BCR-ABL1 in chronic myeloid leukemia affect different leukemic cells

Clonal development of myeloproliferative disorders: clues to hematopoietic differentiation and multistep pathogenesis of cancer

Tyrosine kinase inhibitor therapy can cure chronic myeloid leukemia without hitting leukemic stem cells

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