Srdan Verstovsek, MD, PhD
Professor of Medicine
Department of Leukemia
Division of Cancer Medicine
Loss of LKB1/STK11 Facilitates Leukemic Progression of the Myeloproliferative Neoplasms
Blood (2020) 136 (Supplement 1): 1.
Leukemic progression of the Philadelphia chromosome-negative Myeloproliferative Neoplasms (MPNs) to acute myeloid leukemia (AML; defined by the presence of blasts ≥20% in the bone marrow or peripheral blood) is also known as MPN in blast phase (MPN-BP) . Nearly always, MPN-BP evolves from chronic phase MPN via an intervening accelerated phase (MPN-AP) with blasts ≥10-19% [2, 3]. The classic MPNs consist of primary myelofibrosis (PMF), which is the most aggressive (life expectancy 5-7 years), and two relatively indolent subtypes, polycythemia vera (PV) and essential thrombocythemia (ET). The reported frequencies of leukemic progression varies from ~20% for PMF to ~8% for PV and ~2% for ET. Clinically, MPN-BP prognosis is very poor (the worst among all subtypes of AML) with a median overall survival of about ~6-9 months. Currently, there is no effective therapy that would significantly prolong survival of patients in MPN-BP except for allogeneic hematopoietic cell transplantation (possible in a very low percent of patients) .
Evidently, understanding the risk of leukemic progression for patients in chronic-phase MPN is of significant value, possibly leading to a different therapeutic approach in such patients (e.g., intervention with the option of transplant sooner rather than later). Several factors significantly affect the risk of leukemic transformation and have been included in a variety of prognostic scoring systems ; among them, the mutational profile during chronic-phase MPN appears to be a major contributor to transformation risk [6, 7]. Furthermore, MPN-BP is characterized by a marked mutational profile in comparison to de novo AML [1, 8]. The mechanisms of leukemic progression have not been fully elucidated and may differ among different patients [1, 9]. This knowledge, however, may inform us about possible new ways to not only predict progression but also lead to discovery of novel ways to tackle therapeutically these significant biological parameters and develop effective new therapies.
In this regard, Christian Marinaccio and colleagues presented novel results on the possible role of serine/threonine kinase 11 (STK11; also known as liver kinase B1, LKB1) in collaboration with activated JAK/STAT signaling in leukemogenesis . Data suggest that STK11/LKB1 is a tumor suppressor in leukemic progression of MPN given that its loss is a driver of progression. In a specific mouse model, Stk11 loss led to marked changes in gene expression in MPL W515L cells (which are cells causing MPN). One upregulated gene was a target of hypoxia-inducible factor (HIF). HIF1α is stabilized by and sufficient for proliferation, enhancing a lethal MPN phenotype in MPL W515L mice that showed intense osteosclerosis, bone marrow failure, and pockets of undifferentiated, immature cells. Furthermore, loss of STK11 (by CRISPR/Cas9) enhanced engraftment of human MPN cells in NSGS (immunocompromised) mice. Finally, in 7 paired chronic versus MPN-BP samples from patients with MPN, STK11 expression was downregulated in 5 of 7 in BP, with marked increase of HIF1α expression, among other gene expression differences . Implications of these findings are that pseudohypoxia in MPN-BP, through loss of STK11, might provide new treatment avenues by targeting hypoxia-inducible proteins. This would be a significant advancement given that satisfactory treatment of MPN-BP remains a major unmet medical need [1, 11].