Stem cell origins of JMML

Abstract

In this issue of JEM, Louka et al. (https://doi.org/10.1084/jem.20180853) report that leukemia stem cells lie within the phenotypic hematopoietic stem cell and progenitor cell compartments in juvenile myelomonocytic leukemia (JMML). Furthermore, they identify several candidate biomarker/therapeutic targets, such as CD96 and SLC2A1, that are of translational significance in JMML.

Insights from Sriram Sundaravel and Ulrich Steidl.

Figure 1. Proposed model of JMML hematopoiesis compared with normal hematopoiesis. Hematopoietic hierarchy is depicted by the use of solid gray arrows, and the proposed JMML hematopoietic hierarchy is represented by dotted gray arrows. The +/+ population exhibited shared expression profiles between HSC and GMP and is considered to be locked in an HSC-GMP transition state. HSPC populations such as +/+ and GMPs, which were aberrantly increased in JMML, are specified with a solid black up arrow. Various HSPC populations that harbored aberrant mutational clones are marked by a solid red star. Cell populations that were experimentally demonstrated to induce a JMML-like disease in immune-compromised mice are indicated by a solid black star. The authors demonstrated that all the HSPC subpopulations contained mutant clones; however, only the HSC and +/+ populations were able to induce JMML-like disease when transplanted to immune-compromised mice. It is noteworthy that xenotransplantation of the GMP population didn’t result in JMML-like disease despite successful engraftment, which raises the possibility that the GMPs might not harbor the potential to propagate JMML. Future investigations are needed to further clarify the role of GMP in JMML onset and/or relapse. The genes that are up-regulated in JMML HSC and +/+ populations are depicted using solid green up arrows. CMP, common myeloid progenitor; MEP, megakaryocyte erythroid progenitor.

Figure 2. Proposed model of HSC clonal evolution in JMML. JMML HSCs are clonally dominant with mutations in the RAS pathway genes (KRAS, NRAS, PTPN11, NF1, CBL), which are indicated by a solid red circle. The results also support the presence of subclones, which are indicated by solid blue/orange circles. The authors present evidence supporting linear and/or early branching clonal evolution patterns in JMML.