Deciphering the Pathogenesis of Acute Myeloid Leukemia

Kristian Reckzeh

Deciphering the Pathogenesis of Acute Myeloid Leukemia

Kristian Reckzeh

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Popular Abstract in Swedish
Leukemi är en cancersjukdom i blod och benmärg som karakteriseras av en störd blodbildning. Vid normal blodbildning delar sig ett begränsat antal omogna blodceller så kallade blod stamceller (eller hematopoietiska stamceller) och mognar till funktionella blodceller. Genom att dela sig utan att mogna har stamcellerna även potential till at förnya sig själva. När nya stamceller och mogna celler samtidigt bildas kan en kontinuerlig blodproduktion upprätthållas genom livstiden. Då leukemi uppstår mognar blodcellerna inte fullt ut, vilket leder till en anhopning av omogna celler med brist av funktionella blodceller som följd. Ett fåtal leukemiska stamceller tros ligga bakom den maligna expansionen. Konventionell leukemibehandling minskar mängden omogna celler men förefaller inte vara verksam på de leukemiska stamcellerna. De leukemiska stamceller som blir kvar efter behandling förmodas vara den bakomliggande orsaken till återfall. Akut myeloisk leukemi (AML) är en typ av leukemi där man känner till flera genetiska förandringar (mutationer) som förekommer i de maligna blodcellerna. För att bättre kunna forstå uppkomst av AML har vi upprättat en musmodell för human AML genom att föra in tre vanligt förekommande mutationer i det genetiska materialet hos musens blodceller. Vår modell tillåter molekylära och cellulära studier både före och under manifestationen av sjukdomen. Jämfört med tidigare modeller representerar vår modell orsaken till leukemien på ett bättre sätt.
Våra resultat och de framtida studier de kommer att leda till kan bidra till nya framtida terapier i kampen mot AML. Dessutom kan musmodellen användas för att studera innovativa och oprövade läkemedel.

Originalspråk	engelska
Kvalifikation	Doktor
Tilldelande institution	Medicinska fakulteten
Handledare	Cammenga, Jörg, handledare Karlsson, Stefan, handledare Juliusson, Gunnar, handledare
Tilldelningsdatum	2012 maj 3
Förlag	Division of Molecular Medicine and Gene Therapy, Dept of Laboratory Medicine
ISBN (tryckt)	978-91-86871-99-4
Status	Published - 2012

Bibliografisk information

Defence details

Date: 2012-05-03
Time: 10:00
Place: Belfragesalen, D15, BMC.

External reviewer(s)

Name: Porse, Bo
Title: [unknown]
Affiliation: Finsen Laboratory, University of Copenhagen

---

Ämnesklassifikation (UKÄ)

Hematologi
Medicin och hälsovetenskap

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1 Artikel i vetenskaplig tidskrift

Molecular and cellular effects of oncogene cooperation in a genetically accurate AML mouse model.
Reckzeh, K., Bereshchenko, O., Mead, A., Rehn, M., Kharazi, S., Jacobsen, S. E. W., Nerlov, C. & Cammenga, J., 2012, I: Leukemia. 26, 7, s. 1527-1536
Forskningsoutput: Tidskriftsbidrag › Artikel i vetenskaplig tidskrift › Peer review

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@phdthesis{33d32ebd082c424e872519e3f0c6a4b7,

title = "Deciphering the Pathogenesis of Acute Myeloid Leukemia",

abstract = "Acute myeloid leukemia (AML) is a malignant disorder of the blood system. Hematopoietic stem cells (HSCs) supply and maintain this system by differentiating via intermediates into lineage-restricted progenitors that strongly proliferate to keep up with the high turn-over of mature blood cells. In AML, the mechanisms controlling differentiation and proliferation of myeloid cells are disturbed leading to the accumulation of undifferentiated cells that interfere with the production of normal blood cells. Mutations of the transcription factor C/EBPα have been observed in 10 percent in AML with normal cytogenetics. In addition, internal tandem duplications (ITD) of FLT3 are frequently observed alterations in AML and coincide with mutations of C/EBPα. The effects of FLT3-ITD cooperation with C/EBPα mutations in AML are not fully understood. To address this, knockin mouse strains harboring different Cebpa mutations and Flt3-ITD were used to generate an AML mouse model. This model demonstrated a block at the transition from pGMP to GMP due to disrupted C/EBPα function. The cooperative effect of FLT3-ITD is composed of enhancing the generation of leukemia-initiating GMPs and activation of STAT5 targets. In in vitro studies it was demonstrated that FLT3-ITD reduces the cytokine-requirements for cell growth and that leukemic cells harboring FLT3-ITD are more sensitive to inhibition of the FLT3 pathway in vitro. To address the impact of FLT3-ITD gene dosage and loss of Flt3 wild type allele in vivo the Flt3-ITD knockin mouse was crossed to the Flt3 receptor knockout mouse. These studies demonstrated that the myeloproliferative phenotype was FLT3-ITD dosage-dependent and independent of FL. In summary, the data presented provide deeper insights into oncogene cooperation and FLT3-ITD dosage in AML.",

keywords = "Hematopoiesis, Hematopoietic Stem Cell, AML, FLT3, C/EBPalpha",

author = "Kristian Reckzeh",

note = "Defence details Date: 2012-05-03 Time: 10:00 Place: Belfragesalen, D15, BMC. External reviewer(s) Name: Porse, Bo Title: [unknown] Affiliation: Finsen Laboratory, University of Copenhagen ---",

year = "2012",

language = "English",

isbn = "978-91-86871-99-4",

series = "Lund University Faculty of Medicine Doctoral Dissertation Series ",

publisher = "Division of Molecular Medicine and Gene Therapy, Dept of Laboratory Medicine",

type = "Doctoral Thesis (compilation)",

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T1 - Deciphering the Pathogenesis of Acute Myeloid Leukemia

AU - Reckzeh, Kristian

N1 - Defence details Date: 2012-05-03 Time: 10:00 Place: Belfragesalen, D15, BMC. External reviewer(s) Name: Porse, Bo Title: [unknown] Affiliation: Finsen Laboratory, University of Copenhagen ---

PY - 2012

Y1 - 2012

N2 - Acute myeloid leukemia (AML) is a malignant disorder of the blood system. Hematopoietic stem cells (HSCs) supply and maintain this system by differentiating via intermediates into lineage-restricted progenitors that strongly proliferate to keep up with the high turn-over of mature blood cells. In AML, the mechanisms controlling differentiation and proliferation of myeloid cells are disturbed leading to the accumulation of undifferentiated cells that interfere with the production of normal blood cells. Mutations of the transcription factor C/EBPα have been observed in 10 percent in AML with normal cytogenetics. In addition, internal tandem duplications (ITD) of FLT3 are frequently observed alterations in AML and coincide with mutations of C/EBPα. The effects of FLT3-ITD cooperation with C/EBPα mutations in AML are not fully understood. To address this, knockin mouse strains harboring different Cebpa mutations and Flt3-ITD were used to generate an AML mouse model. This model demonstrated a block at the transition from pGMP to GMP due to disrupted C/EBPα function. The cooperative effect of FLT3-ITD is composed of enhancing the generation of leukemia-initiating GMPs and activation of STAT5 targets. In in vitro studies it was demonstrated that FLT3-ITD reduces the cytokine-requirements for cell growth and that leukemic cells harboring FLT3-ITD are more sensitive to inhibition of the FLT3 pathway in vitro. To address the impact of FLT3-ITD gene dosage and loss of Flt3 wild type allele in vivo the Flt3-ITD knockin mouse was crossed to the Flt3 receptor knockout mouse. These studies demonstrated that the myeloproliferative phenotype was FLT3-ITD dosage-dependent and independent of FL. In summary, the data presented provide deeper insights into oncogene cooperation and FLT3-ITD dosage in AML.

AB - Acute myeloid leukemia (AML) is a malignant disorder of the blood system. Hematopoietic stem cells (HSCs) supply and maintain this system by differentiating via intermediates into lineage-restricted progenitors that strongly proliferate to keep up with the high turn-over of mature blood cells. In AML, the mechanisms controlling differentiation and proliferation of myeloid cells are disturbed leading to the accumulation of undifferentiated cells that interfere with the production of normal blood cells. Mutations of the transcription factor C/EBPα have been observed in 10 percent in AML with normal cytogenetics. In addition, internal tandem duplications (ITD) of FLT3 are frequently observed alterations in AML and coincide with mutations of C/EBPα. The effects of FLT3-ITD cooperation with C/EBPα mutations in AML are not fully understood. To address this, knockin mouse strains harboring different Cebpa mutations and Flt3-ITD were used to generate an AML mouse model. This model demonstrated a block at the transition from pGMP to GMP due to disrupted C/EBPα function. The cooperative effect of FLT3-ITD is composed of enhancing the generation of leukemia-initiating GMPs and activation of STAT5 targets. In in vitro studies it was demonstrated that FLT3-ITD reduces the cytokine-requirements for cell growth and that leukemic cells harboring FLT3-ITD are more sensitive to inhibition of the FLT3 pathway in vitro. To address the impact of FLT3-ITD gene dosage and loss of Flt3 wild type allele in vivo the Flt3-ITD knockin mouse was crossed to the Flt3 receptor knockout mouse. These studies demonstrated that the myeloproliferative phenotype was FLT3-ITD dosage-dependent and independent of FL. In summary, the data presented provide deeper insights into oncogene cooperation and FLT3-ITD dosage in AML.

KW - Hematopoiesis

KW - Hematopoietic Stem Cell

KW - AML

KW - FLT3

KW - C/EBPalpha

M3 - Doctoral Thesis (compilation)

SN - 978-91-86871-99-4

T3 - Lund University Faculty of Medicine Doctoral Dissertation Series

PB - Division of Molecular Medicine and Gene Therapy, Dept of Laboratory Medicine

ER -

Deciphering the Pathogenesis of Acute Myeloid Leukemia

Sammanfattning

Bibliografisk information

Ämnesklassifikation (UKÄ)

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Forskningsoutput

Molecular and cellular effects of oncogene cooperation in a genetically accurate AML mouse model.

Citera det här