Summary Cell Growth and Differentiation - translational (MM1TR)

Summary cell growth & differentiation
– Translational: developmental
disorders and malignancies




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,Chapter 1 Blood cell disorders
Hematopoiesis is the development of blood cells  takes place in the bone marrow
 Hematopoietic stem cells (HSCs) are present in the bone marrow give rise to all blood cells  differentiate in
the BM into progenitor cells
 Differentiation is steered by growth factors  extrinsic
 In combination with transcription factors  stem cell intrinsic
o Intrinsic factors might change over time  might be the reason why children in average
develop lymphoid leukaemia more often than myeloid leukaemia than elderly
 Progenitor cells  referred to as ‘blasts’ remain within the BM and only enter the periphery when
fully differentiated
o Lymphoid
o Myeloid
 HSCs have the capacity to self-renew  very slow division so more Quiescent
 Multi-hit model: mutations passed on to daughter cells
 With each SC division the number of mutations increases
 Commonly used marker for blasts and HSCs is CD34
 Differentiation is tightly regulated  mutations can cause disbalance
 Many genes involved
 Driver mutations: almost all of these are in signalling regulation




Leukaemia vs myelodysplastic syndrome
A quite severe and common developmental disorder in hematopoiesis is leukemia:
 Leukemia is the accumulation of immature cells in the BM  blasts do not leave the BM
 Upregulated proliferation  growth factor independent
 Decreased apoptosis
 And a block in differentiation  leads to accumulation of blasts
 Acute when >20% of cells in the BM are blasts

Myelodysplastic syndrome: we speak of myelodysplastic syndrome when the blood cells have an abnormal shape
but they do differentiate
 Indolent MDS: So unlike in leukaemia cells differentiate
 Aggressive MDS: And with aggressive MDS the cells look dysplastic on top of their blocked differentiation
 Thus can develop into leukaemia at a later stage  we speak of this when differentiation gets
blocked and blasts start accumulating
 Affected lineage differs per patient  hence symptoms differ per patient

Both leukaemia (AML) and myelodysplastic syndrome (MDS) have a higher incidence amongst the elderly which
largely impacts treatment and prognosis.

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, Development of leukaemia
Mutations are acquired due to carcinogenic agents, and naturally during cell division  all mutations in HSCs are
passed on to daughter cells
 Development of leukaemia is a multi-hit process  multiple driver mutations required to acquire the cancer
hallmarks
 These mutations are in genes that regulate the balance between proliferation and apoptosis  give
the cell a growth advantage
o Positive selection leads to mutation co-occurrence
 Causes clonal expansion
 CHIPs might increase the risk for leukaemia because they can be malignant in combination with
other mutations
 Full blown leukaemia is a combination of mutations in 2-3 genes from different categories:
 I: growth factor receptors
 II: signal transduction molecules
 III: gene expression regulation
o TFs
o Epigenetic regulators
o RNA splicing factors
o Chromatin organisation
 IV: apoptosis

Enzymes involved in DNA (de)methylation are often mutated in AML  hypermethylation of promoters for tumour-
suppressor genes or demethylation of proto-oncogenes
 DNMT(3a): copy methylation profile after division  hyperactivity
 Hypomethylating agents: Azacitidine and decitabine are cytosine analogues  incorporated at C-
sites but cannot be methylated
 TET(2) proteins: operate in active demethylation  need α-ketogluterate as a substrate

 IDH1/2: convert α-KG into α-HG
 Inhibitors of IDH1/2 increase α-KG levels




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