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Gene & Protein in Disease BCL11A targets and chromatin binding patterns

in Figure 1B, these genes were also highly expressed in In Figure 2, we present a revised model for pDC
the leukemias analyzed here, with the exception of AXL. development that incorporates preexisting data as well
The observation that AXL is targeted by BCL11A in the as findings from this study and prior work by us and
leukemias but not in CAL-1 pDC controls suggests that others. 7,8,32,34,35 This model (discussed in detail in the legend
32
the well-documented AXL immunosuppressive function 33 to Figure 2) proposes developmental routes originating
might be lost in the leukemias. Together, these data from both the common dendritic progenitor and the
further support the existence of B-pDCs in both mice and CLP – both under BCL11A transcriptional control. We
humans. hypothesize that as CLP progenitors proceed to pre-pro B
cells, a subset of primed B cells diverges to form the spleen-
4. Discussion homing, intrinsically active, AXL SIGLEC1 CD19 B-pDC
+
-
+
We previously observed that, when overexpressed in subset described previously. 7
conventional pDCs, BCL11A directly upregulated ID3 Given the emerging clinical importance of
and indirectly downregulated ID2. The high expression of AXL-mediated immunosuppression, it is unfortunate that
8
ID2 in B-pDCs raises the likelihood that B-pDCs rely on a detailed understanding of its transcriptional regulation
a distinct developmental pathway. The reliance on B-pDC remains largely unknown. While further studies are
36
development on established B-cell transcription factors required, we propose adding BCL11A, at least in leukemias,
(including ID2, ID3, TCF4, and BCL11A) adds complexity to the short list of AXL transcriptional regulators. This
that challenges a linear model of pDC specification. hypothesis aligns with our previous observation of AXL

Figure 2. A detailed model of pDC and B-cell derived pDC development. We propose a two-pronged model for pDC differentiation. Following the split
from multipotent progenitors (MPPs), common dendritic progenitors (CDPs) progress to pDCs by default through constitutive expression of BCL11A
and TCF4 through a feedback loop. In this loop, BCL11A activates TCF4 and ID3 transcription, which, in turn, undergo heterodimerization, leading to
a reduction in the activity of TCF4 (or other E-protein family members). In this way, ID3 (and perhaps BCL11A autoregulation) provides homeostatic
maintenance of pDC by dampening TCF4. In the absence of BCL11A, conventional DC (cDC) persists, and an alternate CMP-CDP-cDC pathway is
favored. Additional direct targets of BCL11A necessary for pDC development include PU.1/SPI1 and SPIB. Second, pDCs can be alternatively generated
from the CLP via an incompletely defined mechanism. These pDCs express increased levels of major histocompatibility class II, possibly under the
direction of ID2 suppression of TCF3, an established promoter of B-cell development, and SPIC suppression of B-cell development (dotted grey lines).
Abbreviations: BCL11A: B-cell lymphoma/leukemia 11A; ID3: Inhibitor of differentiation 3; pDC: Plasmacytoid dendritic cells; SPIC: Spi-C transcription
factor; TCF: Transcription factor.

Volume 4 Issue 2 (2025) 4 doi: 10.36922/gpd.8131