LIN28B overexpression defines a novel fetal-like subgroup of juvenile myelomonocytic leukemia

Abstract

Key Points• LIN28B is overexpressed in about half of juvenile myelomonocytic leukemia patients and defines a novel fetal-like disease subgroup. • LIN28B expression is correlated with high fetal hemoglobin levels and the absence of monosomy 7.Juvenile myelomonocytic leukemia (JMML) is a rare and aggressive stem cell disease of early childhood. RAS activation constitutes the core component of oncogenic signaling. In addition, leukemic blasts in one-fourth of JMML patients present with monosomy 7, and more than half of patients show elevated age-adjusted fetal hemoglobin (HbF) levels. Hematopoietic stem cell transplantation is the current standard of care and results in an event-free survival rate of 50% to 60%, indicating that novel molecular-driven therapeutic options are urgently needed. Using gene expression profiling in a series of 82 patient samples, we aimed at understanding the molecular biology behind JMML and identified a previously unrecognized molecular subgroup characterized by high LIN28B expression. LIN28B overexpression was significantly correlated with higher HbF levels, whereas patients with monosomy 7 seldom showed enhanced LIN28B expression. This finding gives a biological explanation of why patients with monosomy 7 are rarely diagnosed with high age-adjusted HbF levels. In addition, this new fetal-like JMML subgroup presented with reduced levels of most members of the let-7 microRNA family and showed characteristic overexpression of genes involved in fetal hematopoiesis and stem cell self-renewal. Lastly, high LIN28B expression was associated with poor clinical outcome in our JMML patient series but was not independent from other prognostic factors such as age and age-adjusted HbF levels. In conclusion, we identified elevated LIN28B expression as a hallmark of a novel fetal-like subgroup in

Comparison of gene expression profiles between human erythroid cells derived from fetal liver and adult peripheral blood

“…Over-expression of these genes decreases β -globin expression in adult erythroblasts (De Vasconcellos et al, 2017). LIN28B over-expression in cultured adult erythroblasts reduces the expression of let-7 , which in turn leads to increased HbF expression (Helsmoortel et al, 2016; Lee et al, 2013). The expression of genes marking the transition of fetal-to-adult erythropoiesis including CA1, GCNT2, and BCL11A are negatively regulated by LIN28B (Lee et al, 2013).…”

Mice expressing KrasG12D in hematopoietic multipotent progenitor cells develop neonatal myeloid leukemia

“…Consistent with a faithful model of hyperactive RAS-induced JMML, BM enhanced myeloid cell production compared with adult progenitors targeted by Mx1Cre (24,27). This context emulates studies of JMML patients that highlighted the fetal origins of this disease: the causative somatic mutation commonly occurs before birth, and BM cells have a gene expression signature that is characteristic of fetal progenitors (22,23). Therefore, in contrast to Mx1Cre, Flt3Cre targets Kras G12D expression to hematopoietic progenitors at the appropriate developmental stage to recapitulate the origin of JMML.…”

“…Patients present very young with a median age of less than 2 years, and retrospective analyses indicate that the somatic disease-initiating mutation is frequently present at birth (6,21,22). Furthermore, BM progenitors of most patients exhibit a fetal-like gene expression signature, which correlates with an inferior prognosis (23). These findings strongly implicate a developmental origin of JMML and imply that disease-initiating mutations occur within a specific spatial and temporal context.…”

Yolk sac erythromyeloid progenitors expressing gain of function PTPN11 have functional features of JMML but are not sufficient to cause disease in mice

“…Children present very young with a median age of <2 years. Patients frequently have elevated levels of fetal hemoglobin and their bone marrow cells have a gene expression signature characteristic of fetal progenitors (Weinberg et al, 1990; Helsmoortel et al, 2016). Furthermore, retrospective analysis suggests that the majority of somatic JMML-initiating mutations occur before birth (Kratz et al, 2005; Matsuda et al, 2010; Stieglitz et al, 2015).…”