Characterisation of the Leukemic Stem Cell in a Murine Model of CALM/AF10 Positive Myeloid Leukemia

Deshpande, Aniruddha (2006): Characterisation of the Leukemic Stem Cell in a Murine Model of CALM/AF10 Positive Myeloid Leukemia. Dissertation, LMU München: Medizinische Fakultät

Abstract

We have demonstrated, that an acute leukemia with a predominantly myeloid phenotype can be propagated by a progenitor with lymphoid characteristics in a mouse model of the t(10;11) (p13;q14) translocation. Mice transplanted with bone marrow retrovirally engineered to express the leukemia specific CALM/AF10 fusion gene consistently developed an acute leukemia with a short latency. The leukemia showed characteristic myeloid features such as the presence of myeloid marker positive cells infiltrating multiple hematopoietic and non-hematopoietic organs, the positivity of blasts for myeloid specific histochemical stainings and the depletion of the lymphoid compartment in lymphoid organs. Apart from the major population of cells expressing myeloid but not lymphoid markers (M population), a smaller population of cells expressing myeloid markers as well as the lymphoid marker B220 ( B/M population) and a smaller population expressing only the B220 marker (B population) could be detected in all mice. We determined that the frequency of leukemia propagating cells was the highest in the B population and that this population could give rise to the other two populations of cells, namely the B/M and the M populations. This indicated that the leukemic stem cell candidate for the myeloid leukemia in this model of CALM/AF10 induced transformation is a B220 + cell. Further characterization of these candidate LSCs revealed the presence of D-JH rearrangements and the absence of Pax5 transcription. These cells were characterised as being CD43 + /AA4.1 + /HSA low-pos/CD19 -/FLT3R + /IL-7R low-neg c-kit low-neg and expressing the early B cell factor (EBF) transcripts as well as transcripts for the myeloperoxidase (MPO) gene,bearing a resemblance to Pax5 knockout preBI cells. These findings indicate that the leukemia-propagating cell in a subset of acute myeloid leukemias could be a cell with lymphoid characteristics. The fact that this progenitor cell expressed markers different from those expressed by the bulk leukemic population but could still propagate the leukemia raises the interesting possibility of selectively targeting these cells using novel therapeutic strategies that aim to eliminate these LSCs.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: cancer stem cells, leukemia, CALM/AF10, AML
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit ; 600 Technik, Medizin, angewandte Wissenschaften
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 23. Januar 2006
• 1. Bericht­erstatter:in: Bohlander, Stefan