How a rare pediatric neoplasia can give important insights into biological concepts: a perspective on juvenile myelomonocytic leukemia

Abstract

F e r r a t a S t o r t i F o u n d a t i o nderived from peripheral blood or bone marrow of JMML patients form excessive numbers of granulocytemacrophage colonies in vitro even when cultured without exogenous cytokines.12 This phenomenon is known as spontaneous proliferation and depends on the presence of leukemic monocytes.13 Second, dose-response experiments demonstrated that JMML myeloid progenitor cells are hypersensitive to GM-CSF.14 It is likely that constitutive low-level secretion of cytokines, primarily GM-CSF, by leukemic monocytes, coupled with the hypersensitivity of granulocyte-macrophage colony-forming units to these stimuli, is sufficient to drive the excessive myeloproliferation. Although not absolutely specific for JMML, GM-CSF hypersensitivity is a key feature of the disease and has become a valuable diagnostic tool. In addition, it pointed the way to major advances in our understanding of the molecular pathogenesis of JMML. Today, gene mutations interfering with downstream components of the GM-CSF signal transduction pathway can be defined in approximately 70% of children with this disorder.The transmission of GM-CSF signals from its receptor to the nucleus occurs mainly through the sequential phosphorylation of a series of intracellular proteins centered around the RAS signal transduction pathway, 15 as reviewed in more detail by Downward.16 Functioning as cellular master switches, RAS proteins bind guanosine triphosphate (RAS-GTP) in their active configuration and guanosine diphosphate (RAS-GDP) when inactive.17 The cellular levels of active RAS-GTP are balanced within tight boundaries by the concurrent action of guanine nucleotide exchange factors (GNEF) and GTPase-activating proteins (GAP).18 Extracellular stimuli, such as GM-CSF binding to its receptor, activate adaptor molecules (e.g., GRB2, SHC, GAB2) which recruit GNEF (e.g., SOS1) to turn on RAS by displacing GDP and allowing GTP to bind (Figure 2). Active RAS forwards the signal to RAF1, PI3K, RALGDS and other effector molecules.19 RAS itself possesses intrinsic GTPase activity which hydrolyses RAS-GTP to RAS-GDP and thus terminates the signal.20 GAP, most notably the NF1 gene product, neurofibromin, dramatically accelerate this process, serving as molecular brakes on the RAS pathway. 19,20 The following paragraphs will briefly describe how the various genetic lesions observed in JMML result in deregulation of RAS signaling. There are three prominent RAS proto-oncogenes in the human genome, termed NRAS, KRAS and HRAS, which were originally identified as orthologs of rat sarcoma virus oncogenes. Point mutations at codons 12, 13 or 61 of NRAS, KRAS or HRAS are commonly encountered in a broad spectrum of human cancers and leukemias. 21 The mutations affecting these residues lead to RAS proteins with reduced capacity for GTP hydrolysis and resistance to GAP, resulting in overstimulation of RAS-dependent target molecules in the nucleus. In JMML, somatic mutations of the NRAS or KRAS (but not HRAS) genes are found in leukemic cells at dia...

Correlation of Clinical Features With the Mutational Status of GM-CSF Signaling Pathway-Related Genes in Juvenile Myelomonocytic Leukemia

“…In the current study, we confirmed that PTPN11 mutations are the most frequent molecular aberrations (45%) in Japanese children with JMML. If a PTPN11 mutation is present, it is important to rule out the possibility of NS, especially in infants, because the JMML-like disorder in these patients may spontaneously disappear without therapy, so it is considered distinct from common JMML (31). All mutations detected in our cohort were located in exons 3 and 13 of the PTPN11 gene, which accords with previous findings that mutations associated with JMML exist only in these two exons (9,16).…”

Somatic mosaicism for oncogenic NRAS mutations in juvenile myelomonocytic leukemia

“…Somatic mutations in genes involved in GM-CSF signal transduction, such as NRAS, KRAS, PTPN11, NF1, and CBL, have been identified in more than 70% of children with JMML. [1][2][3] The term "somatic mosaicism" is defined as the presence of multiple populations of cells with distinct genotypes in one person whose developmental lineages trace back to a single fertilized egg. 4 Somatic mosaicism of various genes, including some oncogenes, has been implicated in many diseases.…”

Juvenile myelomonocytic leukemia: Rare case

“…Hasta ilk tanı aldığında; trombosit sayısının düşük olması, iki yaşından büyük olma, yüksek HbF düzeyine sahip olması ve kemik iliğinde artmış blast sayısı gibi prognozu olumsuz yönde etkileyen faktörlerin ilk üçü hastamızda mevcuttu. Bu hastalar doğal seyrine bırakılırsa üç yıl içinde %80 kadarı kaybedilir (9). Kök hücre nakli (KİT) ile olguların yaklaşık %50'si yaşamaktadır.…”