The Impact of Cellular Age on Leukaemic Transformation

Chaudhury, S. , Gibson, B. and Keeshan, K. (2016) The Impact of Cellular Age on Leukaemic Transformation. 21st Congress Of The European Hematology Association, Copenhagen, Denmark, 9-12 June 2016. p. 12.

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Background: Treatment of pediatric acute myeloid leukemia (AML) is largely extrapolated from adult trials despite age related disease heterogeneity. Indeed, during healthy ageing there are age related hemopoietic stem and progenitor (HSPC) cell proliferative and differentiative differences. We hypothesise that cellular age influences leukemic transformation, having implications for disease phenotype and response to therapy. Aims: To determine if HSPC age affects oncogene-mediated leukemic transformation. Methods: Murine HSPCs including linsca1+cKit+ (LSK), common myeloid progenitor (CMP) and granulocyte-macrophage progenitor (GMP) cells from fetal liver (FL), 3 week(w), 10w and >60w adult bone marrow were isolated and transduced with the fusion oncogenes Nup98HoxA9 (NH9), AML1ETO (AE) and the mutant FLT3-ITD. Leukemic transformation was assessed in vitro by serial colony forming cell (CFC) assays, by growth in liquid culture and in stromal OP9 co-culture. In vivo leukemogenesis was assessed by transplantation of pre-leukemic LSKs transduced with NH9 after 2 rounds of colony formation (CFC2), into sublethally irradiated C57BL/6 mice. Gene expression was assessed by QPCR using fluidigm technology. Results: NH9 transformed LSKs from all 4 ages in vitro. NH9 did not result in FL CMP and GMP transformation, while post-fetal (3w, 10w and >60w) CMPs and GMPs all transformed. Consistent with this, AE and FLT3-ITD transformed FL LSKs but not FL GMPs in vitro. This suggests that fetal transformation relies on specific features of the LSK that are absent from committed myeloid progenitors, independent from the oncogenic insult. To further assess age related transformation differences, NH9 transformed FL, 3w, 10w and >60w LSKs were assessed for AML in vivo. Older (10 and >60w) transformed cells led to a shorter latency with more penetrance than young (FL and 3w) transformed LSKs. Further, acute lymphoblastic leukemia (ALL) was observed in animals transplanted with FL and 3w transformed LSKs, but not 10w or >60w LSKs, suggesting young LSKs retain a lymphoid bias. As all NH9 transformed LSKs in vitro acquired self-renewal properties, the transformation differences observed in vivo may be cell autonomous or non-cell autonomous via the bone marrow microenvironment. Gene expression analysis of microenvironmental receptors and targets show the BMP pathway is upregulated in 10w and >60w LSK transformed cells suggesting the BMP pathway may have a role in age related transformation potential. Summary/Conclusions: While LSKs from all 4 ages acquire self-renewal in vitro, progression to leukemia in vivo is slower and less penetrant in young compared to older transformed cells. This is in accordance with the lower incidence of AML in childhood compared to older adults. Activation of the BMP pathway has previously been associated with AML transformation, and our data suggest that the BMP pathway may play a role in the progression to AML specifically in older cells. The observation of ALL specifically in younger transformed LSKs suggests that young HSPCs retain lymphoid programs after myeloid oncogene expression, consistent with the higher incidence of ALL in childhood. Our findings support that age defined therapies are appropriate as HSPC age related biological differences are retained in leukemia and may impact not only disease phenotype but response to therapy

Item Type:Conference or Workshop Item
Additional Information:Abstract published in Haematoligica 101(S1):295
Glasgow Author(s) Enlighten ID:Chaudhury, Dr Shahzya and Keeshan, Dr Karen
Authors: Chaudhury, S., Gibson, B., and Keeshan, K.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
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