Presence of a functional vitamin D receptor does not correlate with vitamin D3 phenotypic effects in myeloid differentiation

Abstract

Although VDR is expressed in all the acute myeloid leukemia cell populations studied, most of these leukemias do not exibit any phenotypic response when exposed to VD. To determine whether VD resistance is related to an altered VDR function, we performed an analysis of VDR expression, phosphorylation, DNA binding capacity and transactivation activity in several leukemic myeloid cell lines arrested at different levels of maturation. Our results indicate that VD induces a clear phenotypic effect, i.e. terminal monocytic differentiation, only in leukemic cells of M2/M3 (intermediate myeloblasts) and M5 (monoblasts) types but not in erythroid precursor cells, early leukemic myeloblasts (M0/M1 type) and promyelocytes (M3 type). VDR expression and function are evident in all the nuclear extracts obtained from the different myeloid cell lines after 12 h of VD treatment, but VD activation of monocytic differentiation is limited to a narrow differentiation window characterized by the M2 type myeloid cellular context.

Correlation between differentiation plasticity and mRNA expression profiling of CD34+-derived CD14− and CD14+ human normal myeloid precursors

“…7,8 This property, referred to as 'lineage switching' or 'intrahematopoietic plasticity', was initially based on the observation that a number of leukemic cell lines undergo phenotypic changes 'in vitro' as a result of specific manipulations such as pharmacological treatments 9,10 or transcription factor overexpression. 11,12 Further reports have subsequently indicated that trans-differentiation processes can be reproduced by using normal CD34 þ -derived myeloid precursors.…”

“…Although this model would imply a univocal fate for a cell that has been already committed to a precise maturation lineage, several reports indicate that hematopoietic precursors are able to transdifferentiate from a lineage to another. 7,8 This biological property of hematopoietic cells, referred to as 'lineage switching' or 'intrahematopoietic plasticity', is essentially based on the observation that a number of leukemic cell lines undergo phenotypic changes 'in vitro' as a result of specific manipulations, such as pharmacological treatments 9,10 and transcription factors overexpression. 11,12 By using this approach, lineage switches between erythroid and myeloid, megakaryocytic and erythroid, or even lymphoid and myeloid cell compartments have been reported.…”

“…7 The first demonstration of an intrahematopoietic lineage switching is probably represented by the observation that HL60 leukemic myeloblasts (M2-M3 type granulocytic precursors), normally differentiating toward granulocytes upon treatment with alltrans retinoic acid (ATRA), undergo monocyte-macrophage maturation when stimulated with 1a, 25 di-hydroxy-vitamin D3 (VD). 10 Since then, other granulocyte precursor cell lines such as the M2 type Kasumi-1 have been reported to undergo mono-macrophage differentiation upon VD stimulation. 9 Based on these observations, the late myeloblast to promyelocyte transition appeared to be the preferential context to induce the trans-differentiation of granulocyte precursors to monocytes, since more undifferentiated M0-M1-type (early myeloblastic) or more mature M3-type (promyelocytic) leukemic myeloid cell lines were unable to undergo the same destiny.…”

A functionally active RARα nuclear receptor is expressed in retinoic acid non responsive early myeloblastic cell lines

“…This hypothesis is also supported by the already reported observation that early leukemic myeloblasts express functional vitamin D3 receptors (VDR), but are unable to differentiate after treatment with VD. 49 Apart from RARa, other transcription factors, such as PU.1, AML1 and C/EBPa, are involved in the regulation of myeloid differentiation. 4 Furthermore, several transcription regulatory elements, including the RAREs, have been shown to lie inside the promoter region of certain myeloid related genes, allowing to hypothesize that the expression of such genes is cooperatively activated by the interested transcription factors.…”

Blast maturity and CD34 expression determine the effects of the differentiating agents KH1060 and 9-cis-retinoic acid on the differentiation and clonogenicity of non-M3 acute myeloid leukaemia cells

“…12 In leukaemic cells RXR also forms heterodimers with the vitamin D receptor (VDR). 29 VDR ligation induces CD11b expression in U937 cells. 30 Specific effects of KH1060 in VDR pathways are not yet characterised.…”