The G S mutation is extremely rare

The G571S mutation is extremely rare. In the study by Ma et al. [6] approximately 20,000 blood samples from patients with suspected myeloproliferative neoplasms were analyzed for JAK2 mutations. The G571S mutation was found in only 3 samples, compared to the V617F mutation which was positive in 4280 samples. A recent report describes a family with germline G571S mutations [10], none of whom showed erythrocytosis. The G571S mutation was also found in two patients with “triple-negative” ET and PMF [9]. To our knowledge this is the first case description of a patient with erythrocytosis and a G571S JAK2 mutation. Based on the limited penetrance [10] and in vitro studies [9], it is unlikely that the G571S mutation is the sole driver of erythropoiesis. We hope that this report will facilitate additional studies of patients with the G571S and related am630 13 JAK2 mutations, so as to ascertain their role in the pathogenesis of myeloproliferative disorders.
Introduction Leukemia which occurs in the first month of life (congenital leukemia) is a rare event, with an estimated incidence of 1 in 5 million births [1]. Congenital leukemias constitute a subset of infant leukemia where a significant percentage of cases show rearrangements involving the MLL (KMT2A) oncogene [2]. These rearrangements presumably arise in utero, and this leukemia subtype is notable for having the lowest somatic mutation burden of any human malignancy measured thus far [3]. Despite this, outcomes remain poor, and novel approaches to the treatment of this leukemia are needed. We describe an unusual case of congenital leukemia with lineage switch following treatment, CNS involvement, and a cryptic MLL rearrangement detectable only by RT-PCR.
Case study A full term male was born to a 29-year-old G2P2 mother with an unremarkable prenatal course. He was 7 pounds 14 ounces at birth with normal APGAR scores at 1 and 5min. On physical exam, he was noted to have nodular purpuric lesions on his trunk and face, despite a non-traumatic delivery, and marked hepatosplenomegaly. A complete blood count showed a white blood cell count (WBC) of 126K/µL, hemoglobin of 16.7g/dL, platelet count of 23K/µL, and 47% circulating lymphoblasts (Fig. 1A). Flow cytometric immunophenotyping showed the circulating blasts expressed CD19, CD20, CD22, CD24 partial, HLA -DR, CD34, and TdT. There was variable expression of the myeloid markers CD15 and CD33. The blasts were negative for CD3, CD10, MPO, and all other T-cell, myeloid, and monocytic markers evaluated, including CD14, CD64, and CD7 (Fig. 1C). A diagnosis of B-lymphoblastic leukemia was made. Cytogenetics testing did not reveal any karyotypic abnormalities, and FISH studies were negative for MLL rearrangement (break apart probes), BCR-ABL fusion, ETV6-RUNX1 fusion, and showed disomy for chromosomes 4, 10 and 17. A cerebrospinal fluid sample taken at diagnosis was positive for lymphoblasts (700 WBC/mm3, 39% blasts; 64,000 RBC/mm3). Because the lumber puncture was traumatic, the patient did not meet criteria for CNS3 disease based on the Steinherz/Bleyer algorithm where the CSF WBC/RBC needs to be greater than 2 times blood WBC/RBC. Therefore, the patient was classified as CNS2c. One month later the patient developed leukocytosis (WBC 46K/µL) with 70% blasts and was re-induced to treat the persistent B-lymphoblastic leukemia. A post re-induction bone marrow performed at day +130 found 6% lymphoblasts with the same flow cytometric immunophenotype found at diagnosis. However, karyotyping demonstrated a subset of cells with clonal evolution: 46, XY,+6[2]/46, XY[18]. The chemotherapy was then modified to a regimen of vinorelbine, mitoxanthrone, dexamethasone and Bortezomib[4]. A bone marrow evaluation following re-induction with the modified regimen (day +180) revealed 33% blasts, this time with monocytic features by morphology (Fig. 1B). Rare lymphoblasts were also present; cytochemical staining for MPO was negative in all blasts. A repeat RT-PCR for t(11;19)(q23;p13) was again positive. Flow cytometric immunophenotyping confirmed the morphologic impression of blast monocytic lineage; there was a small subset of blasts with an immunophenotype consistent with the original B-ALL, and a much larger subset of blasts expressing CD2 dim, CD4 partial, CD7, CD56, CD22 dim, CD13 partial, CD15, CD33, CD117 partial, CD14, CD64, and CD38 bright. These blasts were negative for CD19, CD10, CD24, and TdT, and expressed dim MPO, an immunophenotype consistent with monocytic blasts (Fig. 1D). A subsequent cerebrospinal fluid (CSF) specimen demonstrated significant leukocytosis (36 WBC/mm3; 1 RBC/mm3) with 96% promonocytes with atypical morphologic features, suggesting CNS involvement by the lineage switched leukemia. We performed chromosomal microarray analysis (CMA) analysis using CytoScan HD arrays from Affymetrics (Affymetrics, Santa Clara, CA) on the patient\'s sample obtained at the time of relapse, (day +180) to interrogate the MLL and MLLT1 loci for deletions and duplications that may have arisen during the rearrangement which created the MLL-MLLT1 fusion detected by RT-PCR. This analysis revealed a copy number gain (duplication), involving the entire chromosome 6, which was consistent with the presence of the clone with trisomy 6 observed by karyotyping. No deletions or duplications were observed at the MLL and MLLT1 loci. Similarly, CMA analysis did not reveal any pathogenic, disease associated copy number abnormalities (CNA) at other genomic regions, consistent with the previously reported low CNA burden in MLL-rearranged ALL in infants [5].