The role of JARID2 in normal and malignant hematopoiesis: The PRC2 component JARID2 is dispensable for hematopoietic stem cells but critical for the maintenance of leukemic stem cells

Hematopoietic stem cells (HSCs) are under tight transcriptional regulation ensuring proper
function and maintenance of key features such as self-renewal and multi-lineage reconstitution
potential. Erroneous regulation can confer unwanted properties to the cells and ultimately lead
to malignant transformation. Correct regulation is carried out by a variety of transcription
factors and epigenetic regulators. Several studies have implicated the epigenetic modulator
Polycomb Repressive complex 2 (PRC2), responsible for the deposition of the H3K27me3 mark
associated with transcriptional repression, in preserving correct HSC maintenance. Aberrant
function is shown to influence malignant transformation and propagation of disease. A number
of PRC2 auxiliary factors has been identified, one being JARID2, which is involved in
modulating the activity of the complex by regulating binding to target genes.
In contrast to the other PRC2 members, the functional consequences of JARID2 loss in
adult hematopoiesis is largely unknown. Using a genetic model, we investigated the hematopoietic
consequences of Jarid2 deletion. We found that JARID2 is dispensable for the numbers
and function of adult hematopoietic stem cells and observed only mild changes for the downstream
progenitor cells. These findings were further supported by a lack of changes in gene
expression and H3K27me3 levels in these cells. Through transplantation assays, we found that
the self-renewal capacity of normal HSCs are also intact after loss of JARID2.
These findings are in stark contrast to the requirement for JARID2 in the leukemic setting.
In a model of NOTCH1-induced T-ALL we observed an initial acceleration of leukemic onset,
possibly explained by improved homing abilities of the Jarid2 / cells. However, / TALL
showed a marked decrease in the ability to propagate leukemia in secondary recipients.
Furthermore, gene expression profiles for these cells were inversely correlated with relapse signatures
for childhood T-ALL and the increased latency was reflected in a dramatic reduction
in leukemic stem cells (LSC) frequency.
Surprisingly, the latencies were reverted upon re-transplantation into tertiary recipients, and
this corresponded to a rise in LSC numbers. To study this further we performed exome sequencing
of serially transplanted T-ALL and identified mutations in Pten, Ikzf1 and Smo
likely responsible for rescuing the LSC deficiency observed for JARID2 depleted T-ALL.
In summary our findings suggest that contrary to the other PRC2 components, JARID2 is
dispensable for normal HSC function, but vital for the LSC maintenance in NOTCH1 induced T-ALL