Juvenile myelomonocytic leukemia

106

112

The syndrome of leukocyte adhesion deficiency (LAD) combined with a severe Glanzmann-type bleeding disorder has been recognized as a separate disease entity. The variability in clinical and cell biological terms has remained largely unclear. We present data on 9 cases from 7 unrelated families, with 3 patients being actively followed for more than 12 years. The disease entity, designated LAD-1/ variant syndrome, presents early in life and consists of nonpussing infections from bacterial and fungal origin, as well as a severe bleeding tendency. This is compatible with 2 major blood cell types contributing to the clinical symptoms (ie, granulocytes and platelets). In granulocytes of the patients, we found adhesion and chemotaxis defects, as well as a defect in NADPH oxidase activity triggered by unopsonized zymosan. This last test can be used as a screening test for the syndrome. Many proteins and genes involved in adhesion and signaling, including small GTPases such as Rap1 and Rap2 as well as the major Rap activityregulating molecules, were normally present. Moreover, Rap1 activation was intact in patients' blood cells. Defining the primary defect awaits genetic linkage analysis, which may be greatly helped by a more precise understanding and awareness of the disease combined with the early identification of affected patients.

Section: Org Frommentioning

confidence: 99%

Natural history and early diagnosis of LAD-1/variant syndrome

Kuijpers

Bruggen

Kamerbeek

et al. 2006

106

112

“…[10][11][12][13][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.…”

Section: Introductionmentioning

confidence: 99%

The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease

Kratz

Niemeyer

Castleberry

et al. 2005

231

196

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...

“…Currently, the diagnosis is made by meeting a constellation of clinical and laboratory criteria, 1,9 including the demonstration of fewer than 20% blasts in the bone marrow (BM). Historically, patients with JMML treated with conventional chemotherapy have an event-free survival of less than 15%.…”

Section: Introductionmentioning

confidence: 99%

“…Historically, patients with JMML treated with conventional chemotherapy have an event-free survival of less than 15%. 9,10 Allogeneic hematopoietic stem cell transplantation (HSCT) will cure up to 50% of patients. 11 Novel treatment approaches are urgently needed for this disease, given the dismal survival with traditional chemotherapy and the severity of late effects that HSCT confers on these young children.…”

Section: Introductionmentioning

confidence: 99%

Development of an allele-specific minimal residual disease assay for patients with juvenile myelomonocytic leukemia

Archambeault

Flores

Yoshimi³

et al. 2008

Juvenile myelomonocytic leukemia is an aggressive and frequently lethal myeloproliferative disorder of childhood. Somatic mutations in NRAS, KRAS, or PTPN11 occur in 60% of cases. Monitoring disease status is difficult because of the lack of characteristic leukemic blasts at diagnosis. We designed a fluorescently based, allele-specific polymerase chain reaction assay called TaqMAMA to detect the most common RAS or PTPN11 mutations. We analyzed peripheral blood and/or bone marrow of 25 patients for levels of mutant alleles over time. Analysis of pre-hematopoietic stem-cell transplantation, samples revealed a broad distribution of the quantity of the mutant alleles. After hematopoietic stem-cell transplantation, the level of the mutant allele rose rapidly in patients who relapsed and correlated well with falling donor chimerism. Simultaneously ana- IntroductionJuvenile myelomonocytic leukemia (JMML) is an aggressive clonal malignancy of young children characterized by overproduction of myeloid lineage cells that infiltrate hematopoietic and nonhematopoietic tissues. 1,2 More than 70% of patients have a mutation in the NF1, RAS, or PTPN11 genes, which encode proteins involved in Ras signaling. 3 Animal models demonstrate that Nf1 Ϫ/Ϫ , Kras G12D , and Ptpn11 D61G mutant mice all develop fatal myeloproliferative disorders that model JMML in vivo and in vitro. [4][5][6][7][8] These observations strongly support the role of hyperactive Ras in initiating JMML.The diagnosis and treatment of patients present great challenges to physicians. Currently, the diagnosis is made by meeting a constellation of clinical and laboratory criteria, 1,9 including the demonstration of fewer than 20% blasts in the bone marrow (BM). Historically, patients with JMML treated with conventional chemotherapy have an event-free survival of less than 15%. 9,10 Allogeneic hematopoietic stem cell transplantation (HSCT) will cure up to 50% of patients. 11 Novel treatment approaches are urgently needed for this disease, given the dismal survival with traditional chemotherapy and the severity of late effects that HSCT confers on these young children.However, defining response to therapy is another major challenge for clinicians. 12 Current response criteria are broadly defined as a decreasing white blood cell count and lessening organomegaly. Detecting minimal residual disease (MRD) in JMML relies on tracking donor chimerism after HSCT. One quantitative donor chimerism tracking method used and reported in JMML involves polymerase chain reaction (PCR) amplification of short tandem repeats with comparison of informative loci. 13 Thus, delivering chemotherapy or novel agents before HSCT is severely limited by our inability to follow disease burden in these patients.Allele-specific oligonucleotide-PCR has been developed to detect single nucleotide substitution levels in various cancers 14 and involves designing primers that will preferentially amplify the mutant allele over the wild-type (WT) allele by exploiting differences in the amplification efficie...