Metachromatic leukodystrophy (MLD) is an inherited demyelinating disease that causes progressive neurologic deterioration, leading to severe motor disability, developmental regression, seizures, blindness, deafness, and death. The disease presents as a late-infantile, juvenile, or adult form. Hematopoietic stem cell transplantation has been shown to slow disease progression. The purpose of this longitudinal study was to evaluate long-term treatment outcomes after unrelated donor umbilical cord blood (UCB) transplantation in pediatric patients according to disease burden and age at onset (ie, late-infantile versus juvenile). Engraftment, survival, treatment-related toxicity, graft-versus-host disease, neurophysiologic measures, and neurodevelopmental function were assessed. To evaluate whether signal intensity abnormalities on magnetic resonance imaging (ie, modified Loes scores) predict post-transplant cognitive and gross motor development, a general linear mixed model was fit to the data. Twenty-seven patients underwent transplantation after myeloablative chemotherapy; 24 patients engrafted after the initial transplantation. Seven patients died of infection, regimen-related toxicity, or disease progression. Twenty patients (6 with late-infantile onset and 14 with juvenile onset) were followed for a median of 5.1 years (range, 2.4 to 14.7). We found that patients with motor function symptoms at the time of transplant did not improve after transplantation. Brainstem auditory evoked responses, visual evoked potentials, electroencephalogram, and/or peripheral nerve conduction velocities stabilized or improved in juvenile patients but continued to worsen in most patients with the late-infantile presentation. Pretransplant modified Loes scores were highly correlated with developmental outcomes and predictive of cognitive and motor function. Children who were asymptomatic at the time of transplantation benefited most from the procedure. Children with juvenile onset and minimal symptoms showed stabilization or deterioration of motor skills but maintained cognitive skills. Overall, children with juvenile onset had better outcomes than those with late-infantile onset. As in other leukodystrophies, early intervention correlated with optimal outcomes. We conclude that UCB transplantation benefits children with presymptomatic late-infantile MLD or minimally symptomatic juvenile MLD.

We conclude that the clinical staging system based solely on signs and symptoms of disease can be used to predict outcomes after umbilical cord blood transplantation. This staging system can be used prospectively to guide physicians unfamiliar with the disorder in evaluating, monitoring, and counseling families about treatment outcomes. The staging will be useful for both patients diagnosed with infantile Krabbe disease because of clinical symptoms and those identified through neonatal screening programs.

SUMMARY Oncogenic mutations of FLT3 and KIT receptors are associated with poor survival in patients with acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPN) and currently available drugs are largely ineffective. Although Stat5 has been implicated in regulating several myeloid and lymphoid malignancies, how precisely Stat5 regulates leukemogenesis, including its nuclear translocation to induce gene transcription is poorly understood. In leukemic cells, we show constitutive activation of focal adhesion kinase (FAK), whose inhibition represses leukemogenesis. Downstream of FAK, activation of Rac1 is regulated by RacGEF Tiam1, whose inhibition prolongs the survival of leukemic mice. Inhibition of the Rac1 effector PAK1 prolongs the survival of leukemic mice in part by inhibiting the nuclear translocation of Stat5. These results reveal a leukemic pathway involving FAK/Tiam1/Rac1/PAK1 and demonstrate an essential role for these signaling molecules in regulating the nuclear translocation of Stat5 in leukemogenesis.

Intracellular mechanism(s) that contribute to promiscuous signaling via oncogenic KIT in systemic mastocytosis and acute myelogenous leukemia are poorly understood. We show that SHP2 phosphatase is essential for oncogenic KITinduced growth and survival in vitro and myeloproliferative disease (MPD) in vivo.Genetic disruption of SHP2 or treatment of oncogene-bearing cells with a novel SHP2 inhibitor alone or in combination with the PI3K inhibitor corrects MPD by disrupting a protein complex involving p85␣, SHP2, and Gab2. Importantly, a single tyrosine at position 719 in oncogenic KIT is sufficient to develop MPD by recruiting p85␣, SHP2, and Gab2 complex to oncogenic KIT. Our results demonstrate that SHP2 phosphatase is a druggable target that cooperates with lipid kinases in inducing MPD. (Blood. 2012; 120(13):2669-2678) IntroductionGain-of-function mutations in KIT receptor in humans are associated with gastrointestinal stromal tumors (GIST), systemic mastocytosis (SM), and acute myelogenous leukemia (AML). [1][2][3][4] An activating KIT receptor mutation of aspartic acid to valine at codon 814 in mice (KITD814V) or codon 816 in humans (KITD816V) results in altered substrate recognition and constitutive tyrosine autophosphorylation leading to promiscuous signaling. 5,6 Consequently, cell lines and primary BM cells that express the oncogenic KITD814V demonstrate ligand-independent proliferation in vitro and myeloproliferative disease (MPD) in vivo. [5][6][7][8][9] However, the intracellular signals that contribute to KITD814V-induced MPD are not known. Although activating mutations of KIT involving the juxtamembrane domain found in GIST are highly sensitive to inhibition by imatinib mesylate (ie, Gleevec), KIT mutations within tyrosine kinase domain found in SM and AML, including KITD816V, are relatively resistant to imatinib treatment. [10][11][12] Thus, it is vital to identify novel drug targets for diseases involving KITD816V mutation.Emerging data suggest an essential role for SHP2 in MPD. SHP2 is a protein tyrosine phosphatase that is encoded by PTPN11 gene and has been implicated in diverse signaling pathways induced by a number of stimuli, including growth factors, cytokines, extracellular matrix, and even cellular stress. [13][14][15] Given that activating mutations in SHP2 have been found in leukemias and solid tumors, 16,17 efforts are ongoing to define the potential efficacy of SHP2 phosphatase inhibition in diseases bearing SHP2 hyperactivation, either because of activating SHP2 mutations or those in which SHP2 collaborates with other oncogenes. Using genetic approaches, including primary BM cells derived from SHP2 Ϫ/Ϫ and Gab2 Ϫ/Ϫ mice and a novel SHP2 inhibitor, II-B08, identified from a focused library of indole-based salicylic acid derivatives, 18 we demonstrate that SHP2 is essential for KITD814V-induced MPD. We further demonstrate that SHP2 constitutively binds to p85␣ and Gab2 in KITD814V-bearing cells, which can be disrupted by II-B08 resulting in impaired ligand-independent growth in vitro a...

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