EBV-associated T/NK-cell lymphoproliferative disease (T/NK-LPD) is defined as

Transient abnormal myelopoiesis (TAM) is a myeloid proliferation resembling acute megakaryoblastic leukemia (AMKL), mostly affecting perinatal infants with Down syndrome. Although self-limiting in a majority of cases, TAM may evolve as non-self-limiting AMKL after spontaneous remission (DS-AMKL). Pathogenesis of these Down syndrome-related myeloid disorders is poorly understood, except for GATA1 mutations found in most cases. Here we report genomic profiling of 41 TAM, 49 DS-AMKL and 19 non-DS-AMKL samples, including whole-genome and/or whole-exome sequencing of 15 TAM and 14 DS-AMKL samples. TAM appears to be caused by a single GATA1 mutation and constitutive trisomy 21. Subsequent AMKL evolves from a pre-existing TAM clone through the acquisition of additional mutations, with major mutational targets including multiple cohesin components (53%), CTCF (20%), and EZH2, KANSL1 and other epigenetic regulators (45%), as well as common signaling pathways, such as the JAK family kinases, MPL, SH2B3 (LNK) and multiple RAS pathway genes (47%).

Juvenile myelomonocytic leukemia (JMML) is an intractable pediatric leukemia with poor prognosis whose molecular pathogenesis is poorly understood, except for somatic or germline mutations of RAS pathway genes, including PTPN11, NF1, NRAS, KRAS and CBL, in the majority of cases. To obtain a complete registry of gene mutations in JMML, whole-exome sequencing was performed for paired tumor-normal DNA from 13 individuals with JMML (cases), which was followed by deep sequencing of 8 target genes in 92 tumor samples. JMML was characterized by a paucity of gene mutations (0.85 non-silent mutations per sample) with somatic or germline RAS pathway involvement in 82 cases (89%). The SETBP1 and JAK3 genes were among common targets for secondary mutations. Mutations in the latter were often subclonal and may be involved in the progression rather than the initiation of leukemia, and these mutations associated with poor clinical outcome. Our findings provide new insights into the pathogenesis and progression of JMML.

Germ line PTPN11 mutations cause 50% of cases of Noonan syndrome (NS). Somatic mutations in PTPN11 occur in 35% of patients with de novo, nonsyndromic juvenile myelomonocytic leukemia (JMML). Myeloproliferative disorders (MPDs), either transient or more fulminant forms, can also occur in infants with NS (NS/MPD). We identified PTPN11 mutations in blood or bone marrow specimens from 77 newly reported patients with JMML (n ‫؍‬ 69) or NS/MPD (n ‫؍‬ 8). Together with previous reports, we compared the spectrum of PTPN11 mutations in 3 groups: (1) patients with JMML (n ‫؍‬ 107); (2) patients with NS/MPD (n ‫؍‬ 19); and (3) patients with NS (n ‫؍‬ 243). Glu76 was the most commonly affected residue in JMML (n ‫؍‬ 45), with the Glu76Lys alteration (n ‫؍‬ 29) being most frequent. Eight of 19 patients with NS/ MPD carried the Thr73Ile substitution. These data suggest that there is a genotype/phenotype correlation in the spectrum of PTPN11 IntroductionThe PTPN11 proto-oncogene encodes Src-homology tyrosine phosphatase 2 (SHP-2), a protein tyrosine phosphatase with a role in signal transduction and hematopoiesis. 1,2 Somatic PTPN11 mutations exist in 35% of juvenile myelomonocytic leukemia (JMML) specimens and are less frequent in other leukemias. 3-6 SHP-2 relays signals from activated growth factor receptors to Ras. PTPN11, KRAS2, NRAS, and NF1 mutations are found in mutually exclusive subsets of patients with JMML. 3,4 These data support the hypothesis that hyperactive Ras signaling plays a central role in JMML.Germ-line PTPN11 mutations cause approximately 50% of cases of Noonan syndrome (NS), 7,8 a congenital disorder characterized by facial anomalies, short stature, and heart defects. 9 Whereas NS is frequently inherited as an autosomal dominant condition, almost half of the constitutional PTPN11 mutations found in NS arise sporadically. Germ-line PTPN11 mutations are also found in patients with multiple lentigene syndrome (LS), a rare developmental disorder clinically related to NS. 9 Infants with NS are predisposed to developing a myeloproliferative disorder (NS/MPD), which may regress without treatment or follow an aggressive clinical course similar to JMML. 10-14 By contrast, cases of JMML that arise in patients without NS have a poor prognosis without hematopoietic stem cell transplantation. [15][16][17][18] Recent studies show that children with JMML have improved outcomes when they are treated aggressively early in the course of disease. 18 Therefore, differentiating JMML from NS/MPD and identifying patients with NS/MPD who will require aggressive treatment are important clinical questions. We identify PTPN11 mutations in 77 newly reported patients with JMML and NS/MPD, and compare the mutational spectrum in JMML, NS/MPD, and NS/LS to determine if genotype-phenotype correlations exist that may help guide diagnosis and clinical management. Study designTissue samples (bone marrow, peripheral blood, and, rarely, buccal swab and skin fibroblasts) from patients with JMML and NS/MPD were collected under Institutional...

Purpose Acquired somatic uniparental disomy (UPD) is commonly observed in myelodysplastic syndromes (MDS), myelodysplastic/myeloproliferative neoplasms (MDS/MPN), or secondary acute myelogenous leukemia (sAML) and may point toward genes harboring mutations. Recurrent UPD11q led to identification of homozygous mutations in c-Cbl, an E3 ubiquitin ligase involved in attenuation of proliferative signals transduced by activated receptor tyrosine kinases. We examined the role and frequency of Cbl gene family mutations in MPN and related conditions. Methods We applied high-density SNP-A karyotyping to identify loss of heterozygosity of 11q in 442 patients with MDS, MDS/MPN, MPN, sAML evolved from these conditions, and primary AML. We sequenced c-Cbl, Cbl-b, and Cbl-c in patients with or without corresponding UPD or deletions and correlated mutational status with clinical features and outcomes. Results We identified c-Cbl mutations in 5% and 9% of patients with chronic myelomonocytic leukemia (CMML) and sAML, and also in CML blast crisis and juvenile myelomonocytic leukemia (JMML). Most mutations were homozygous and affected c-Cbl; mutations in Cbl-b were also found in patients with similar clinical features. Patients with Cbl family mutations showed poor prognosis, with a median survival of 5 months. Pathomorphologic features included monocytosis, monocytoid blasts, aberrant expression of phosphoSTAT5, and c-kit overexpression. Serial studies showed acquisition of c-Cbl mutations during malignant evolution. Conclusion Mutations in the Cbl family RING finger domain or linker sequence constitute important pathogenic lesions associated with not only preleukemic CMML, JMML, and other MPN, but also progression to AML, suggesting that impairment of degradation of activated tyrosine kinases constitutes an important cancer mechanism.