Deregulated Notch and Wnt signaling activates early-stage myeloid regeneration pathways in leukemia

Abstract

Targeting commonly altered mechanisms in leukemia can provide additional treatment options. Here, we show that an inducible pathway of myeloid regeneration involving the remodeling of the multipotent progenitor (MPP) compartment downstream of hematopoietic stem cells (HSCs) is commonly hijacked in myeloid malignancies. We establish that differential regulation of Notch and Wnt signaling transiently triggers myeloid regeneration from HSCs in response to stress, and that constitutive low Notch and high Wnt activity in leukemic stem cells (LSCs) maintains this pathway activated in malignancies. We also identify compensatory crosstalk mechanisms between Notch and Wnt signaling that prevent damaging HSC function, MPP production, and blood output in conditions of high Notch and low Wnt activity. Finally, we demonstrate that restoring Notch and Wnt deregulated activity in LSCs attenuates disease progression. Our results uncover a mechanism that controls myeloid regeneration and early lineage decisions in HSCs and could be targeted in LSCs to normalize leukemic myeloid cell production.

Chronic Interleukin-1 exposure triggers selective expansion ofCebpa-deficient multipotent hematopoietic progenitors

“…Transcriptional analyses revealed that Cebpa deficiency prevents chronic IL-1βdriven activation of myeloid differentiation, as well as metabolic and proteostatic gene programs important for differentiation. Despite the pre-existing molecular priming of MPP3 toward myeloid lineage differentiation (Cabezas-Wallscheid et al, 2014;Pietras et al, 2015), our data show chronic IL-1β further activates these pathways, consistent with the capacity of myeloid lineage progenitors to overproduce myeloid cells in response to 'emergency' cues (Herault et al, 2017;Kang et al, 2020;Manz and Boettcher, 2014).…”

Cohesin mutations are synthetic lethal with stimulation of WNT signaling

“…Myeloid leukemias are frequently characterized by cohesin mutations, particularly in STAG2 . Furthermore, activation of Wnt signaling is associated with transformation in AML ( Wang et al, 2010 ; Beghini et al, 2012 ; Kang et al, 2020 ) and AML patients were identified with mutations in AXIN1 and APC that lead to stabilization of β-catenin ( Erbilgin et al, 2012 ). CMK is a Down Syndrome-derived megakaryoblastic cell line that typifies myeloid leukemias that are particularly prone to cohesin mutation ( Yoshida et al, 2013 ).…”

“…However, expressed transcripts encoding Wnt signaling pathway components did not cluster differently in cohesin-deficient clones compared with parental MCF10A cells, and cohesin mutation-based clustering remained dominant (Figure 6figure supplement 1B). We reasoned that stimulation of Wnt signaling in a more responsive cell type might be necessary to determine how stabilized catenin in cohesin-deficient cells affects transcription.Myeloid leukemias are frequently characterized by cohesin mutations, particularly in STAG2.Furthermore, activation of Wnt signaling is associated with transformation in AML[55][56][57]…”

Cohesin mutations are synthetic lethal with stimulation of WNT signaling

“…Furthermore, activation of Wnt signaling is associated with transformation in AML [53][54][55] and AML patients were identified with mutations in AXIN1 and APC that lead to stabilization of b-catenin [56]. CMK is a Down Syndrome-derived megakaryoblastic cell line that typifies myeloid leukemias that are particularly prone to cohesin mutation [57].…”

“…The identification of PI3K/AKT/mTOR inhibitors in the screen supports this notion.Wnt signals are important for stem cell maintenance and renewal in multiple mammalian tissues[52]. Canonical Wnt signaling is required for self-renewal of leukemia stem cells (LSCs)[55], and is reactivated in more differentiated granulocyte-macrophage progenitors (GMPs) when they give rise to LSCs[53]. Wnt signaling is an important regulator of hematopoietic stem cell (HSC) self-renewal as well[64].…”