The myeloproliferative neoplasms (MPNs) are a group of rare blood disorders characterized by the abnormal production and accumulation of certain types of blood cells in the bone marrow. MPNs arise from genetic mutations in the hematopoietic stem cells (HSCs), leading to uncontrolled growth of a clonal population of cells with enhanced survival and self-renewal capabilities. As a result, there is an overproduction of certain myeloid cells, depending on the MPN subtype. The three main types of MPNs are polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), each presenting with distinct clinical features and complications. PV involves an overproduction of red blood cells, while ET results in an excessive production of platelets. PMF is characterized by the replacement of bone marrow with fibrous tissue, leading to impaired blood cell production. Patients with MPNs face the risk of transformation to acute myeloid leukaemia (AML), and PMF and PV patients are more prone to transformation than ET patients, making them more aggressive. Oncogenic driver mutations in MPN affect genes involved in blood cell production signalling pathways like JAK2, CALR, and MPL. These mutations are typically mutually exclusive, with patients usually carrying only one mutation at a time. The JAK2^V617F mutation is the most common in MPNs, causing dysregulated JAK-STAT signalling and resulting in uncontrolled blood cell proliferation and survival. Although studies have demonstrated a higher oncogene expression in PV patients compared to ET patients, the underlying mechanisms by which the same mutation can result in different diseases with distinct response to treatment (e.g. JAK inhibitor) remain unclear (2).

The bone marrow microenvironment, also known as the HSC niche, plays a crucial role in the regulation of HSCs. This specialized niche provides a supportive environment for HSC maintenance, self-renewal, and differentiation. The HSC niche consists of various cellular and non-cellular components, including stromal cells, endothelial cells, osteoblasts, and extracellular matrix proteins. The niche not only provides physical support but also regulates HSC quiescence, proliferation, and mobilization in response to physiological demands. Importantly, the bone marrow microenvironment can be influenced by systemic factors and disease conditions, which can alter HSC function and contribute to the development of haematological disorders, including MPNs (3). In a recent study, we investigated whether the heterogeneity on bone marrow niches might explain the different pathogenesis and therapy response in MPN subtypes (1).

Bone marrow niche heterogeneity influences MPN pathogenesis

Using bone marrow trephines from newly-diagnosed patients, as well as PDX and MPN mouse models, we observed that ET HSCs tend to be closer to the bone surface compared to PV HSCs. This was confirmed by intravital imaging experiments in which DsRed-labelled ET or PV HSCs were injected into irradiated recipients and tracked in the mouse skull bone marrow. Furthermore, we found distinct microenvironment remodelling in these MPN subtypes, with ET showing increased arterioles and bone formation, while PV exhibited enlarged central bone marrow sinusoids. Importantly, HSCs in ET were found to be located near arterioles, while PV HSCs were found near sinusoids. These findings highlight the differential niche preferences and microenvironmental changes associated with the JAK2^V617F mutation in ET and PV (1).

We wondered if the location of the HSCs could impact the disease phenotype and evolution. For this, we used mice lacking the β3-adrenergic receptor (β3-AR KO), which exhibit a premature aging of the bone marrow microenvironment manifested by reduced bone-associated (endosteal) vessels and expansion of central bone marrow vessels that favor myelopoiesis (4). Transplant of ET cells in β3-AR KO mice accelerated ET development, which was explained by central bone marrow expansion of HSCs and progenitor cells committed to the megakaryocyte lineage (1). These findings suggest that the microenvironment plays a significant role in modulating the expansion of mutant cells driving MPNs.

ET and PV HSCs exhibit alterations in JAK-STAT-dependent CDC42 polarity

ET and PV patients respond differently to the JAK inhibitor ruxolitinib (5-7), but the reasons are unclear. Ruxolitinib treatment of PV patients and mouse model restored the endosteal niche, increased HSC quiescence, and expanded bone marrow arterioles. Conversely, ruxolitinib treatment relocated multipotent progenitors to the central bone marrow niche, resulting in the enlargement of central sinusoids, in human or murine ET. These findings suggest that the response to JAK inhibition is influenced by distinct HSC-niche interactions, potentially explaining the differential therapeutic effects of ruxolitinib in PV and ET. Additionally, similar effects were observed in CALR-mutant ET or wild-type mice, indicating that ruxolitinib alters the location of HSCs and their microenvironment regardless of JAK2^V617F mutation status (1).

In search of a mechanism explaining the different location in ET and PV HSCs, a transcriptomic analysis and high-resolution microscopy on HSCs revealed an abnormal expression and cell polarity of the small Rho-GTPase CDC42, which regulates important aspects of HSC biology, including niche location, cell migration, polarity, aging, and myelopoiesis (8). We found a premature loss of CDC42 polarity in PV HSCs. Treatment with a CDC42 inhibitor restored HSC polarity and relocated PV-like HSCs to the endosteal bone marrow, leading to increased quiescence and reduced blood counts, effectively reducing myelofibrosis development. JAK-STAT signalling differentially regulated HSC polarity in WT, ET, and PV HSCs. Specifically, STAT1 hindered CDC42 polarity, while STAT5 protected it in WT HSCs. PV-like HSCs exhibited increased basal p-STAT5 activation, which was associated with the loss of CDC42 polarity. In contrast, unphosphorylated STAT5 maintained CDC42 polarity in WT and ET HSCs (1).

These findings highlight the role of JAK-STAT-dependent CDC42 polarity in regulating HSC polarity and niche interactions in MPNs, providing new insights on the different pathogenesis and therapy response in MPN subtypes (1).

REFERENCES

1. Grockowiak E, Korn C, Rak J, Hallou A, Lysenko V, Panvini FM, et al. Different niches for mutant stem cells affect pathogenesis and therapy response in myeloproliferative neoplasms. Nat Cancer. 7 Aug 2023. DOI 10.1038/s43018-023-00607-x.
2. Méndez-Ferrer S, Fang Z. Myeloproliferative Neoplasms. In: Bradshaw RA, Hart GW, Stahl PD, editors. Encyclopedia of Cell Biology (Second Edition). Oxford: Academic Press; 2023. p. 696-711.
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