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  • 1
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 85-85
    Abstract: SHP-2 is a nonreceptor protein tyrosine phosphatase (PTPase) that is essential for embryonic hematopoiesis. SHP-2 acts as a signal relay molecule downstream of diverse growth factor receptors, and potentiates the activity of the Ras/Raf/MAPK pathway. Epistasis studies in model organisms indicate that SHP-2 can act upstream, downstream or parallel to Ras; however, most mammalian systems place SHP-2 upstream of Ras activation. Activating mutations in PTPN11, the gene encoding SHP-2, comprise the most common genetic lesion in juvenile myelomonocytic leukemia (JMML). Other etiologies of JMML include activating mutations in NRAS or KRAS2 and inactivation of the tumor suppressor NF1, which encodes a negative regulator of Ras, supporting a model in which SHP-2 activates Ras in hematopoietic progenitors. We tested the hypothesis that SHP-2 is essential in hematopoiesis because it is required for Ras activation. To do this, we bred mice with conditional hyperactive KrasG12D and inactive Ptpn11flox alleles, in conjunction with the inducible Mx1-Cre transgene. Myeloid progenitors in LSL-KrasG12D; Ptpn11flox/flox; Mx1-Cre mice never deleted both Ptpn11 alleles despite efficient Cre induction and expression of activated K-RasG12D. This indicates selective pressure to retain SHP-2 despite Ras activation and implies that Ptpn11 loss is epistatic to KrasG12D. To test this directly, we acutely disrupted Ptpn11 and expressed KrasG12D in fetal liver cells using Cre-expressing retroviruses, and tested them for myeloid colony-forming activity. This confirmed the need for SHP-2 in myeloid progenitors, and KrasG12D again failed to alleviate this requirement. Surprisingly, expression of either wild type or PTPase-deficient SHP-2 rescued colony growth and restored the aberrant growth of KrasG12D mutant cells. To test whether hematopoiesis in vivo is independent of SHP-2 PTPase function, we created chimeric Mx1-Cre, Ptpn11flox/flox mice in which a small fraction of bone marrow expressed exogenous SHP-2 and GFP. These mice were treated with a short course of pIpC to induce Cre and disrupt Ptpn11, and the contribution of SHP-2 expressing cells in the peripheral blood was monitored by flow cytometry. As expected, exogenous SHP-2 expression in Mx1-Cre, Ptpn11flox/flox bone marrow conferred a strong and durable ( 〉 16 wks) competitive advantage after pIpC treatment. Expression of PTPase-deficient SHP-2 also conferred a strong advantage lasting at least several weeks, and these mice are being aged to determine the duration of this response. These data indicate that SHP-2 is required for growth of both normal and neoplastic myeloid progenitors in vivo and in vitro, and suggest that SHP-2 is needed for maintenance of adult hematopoietic stem cells. In contrast to nearly all prior studies in mammalian cells, our data support a model in which SHP-2 has essential hematopoietic functions downstream or parallel to Ras activation. Furthermore, SHP-2 PTPase activity is not required in myeloid progenitors, a finding which also contradicts widely accepted models of SHP-2 function and may indicate that SHP-2 serves an adaptor role. Because PTPase activity is required by leukemogenic but not wild type SHP-2, pharmacologic PTPase inhibition may selectively target neoplastic hematopoietic progenitors.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 2
    In: Blood, American Society of Hematology, Vol. 117, No. 16 ( 2011-04-21), p. 4253-4261
    Abstract: Src homology 2 domain-containing phosphatase 2 (Shp2), encoded by Ptpn11, is a member of the nonreceptor protein-tyrosine phosphatase family, and functions in cell survival, proliferation, migration, and differentiation in many tissues. Here we report that loss of Ptpn11 in murine hematopoietic cells leads to bone marrow aplasia and lethality. Mutant mice show rapid loss of hematopoietic stem cells (HSCs) and immature progenitors of all hematopoietic lineages in a gene dosage-dependent and cell-autonomous manner. Ptpn11-deficient HSCs and progenitors undergo apoptosis concomitant with increased Noxa expression. Mutant HSCs/progenitors also show defective Erk and Akt activation in response to stem cell factor and diminished thrombopoietin-evoked Erk activation. Activated Kras alleviates the Ptpn11 requirement for colony formation by progenitors and cytokine/growth factor responsiveness of HSCs, indicating that Ras is functionally downstream of Shp2 in these cells. Thus, Shp2 plays a critical role in controlling the survival and maintenance of HSCs and immature progenitors in vivo.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 3
    Online Resource
    Online Resource
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-16), p. 635-635
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 635-635
    Abstract: Activating mutations in PTPN11, which encodes the tyrosine phosphatase SHP-2, comprise the most frequent genetic lesion in juvenile myelomonocytic leukemia (JMML). Other etiologies of JMML include activating mutations in NRAS or KRAS2 and inactivation of the tumor suppressor NF1. These and other observations imply that PTPN11 functions in a common genetic pathway with RAS and NF1. Ras proteins are signal switch molecules that respond to extracellular stimuli by cycling between inactive GDP-bound and active GTP-bound conformations. Oncogenic alleles encode proteins that preferentially accumulate in the GTP-bound form. While NF1 encodes a GTPase activating protein for Ras that directly modulates Ras-GTP levels, the biochemical relationship between SHP-2 phosphatase activity and Ras signaling remains unclear. Most mammalian systems place SHP-2 upstream of Ras activation, but the mechanism is not known. Studies of Ptpn11 mutant embryos and of chimeric mice have shown that SHP-2 plays an essential role in hematopoietic development. We tested the hypothesis that the essential function of SHP-2 in primary hematopoietic cells is to activate Ras. To do this, we determined if Ras activation by expression of an oncogenic Kras2 allele could eliminate the requirement for SHP-2. We used conditional alleles of Kras2 (LSL-KrasG12D) and Ptpn11 (Ptpn11flox/flox) coupled with the inducible Mx1-Cre transgene. Juvenile mice were injected with polyI:polyC, resulting in expression of K-RasG12D and inactivation of Ptpn11. Although these mice uniformly developed fatal MPD similar to what we previously reported in Mx1-Cre, LSL-KrasG12D mice (Braun et al., PNAS 101(2):597–602), myeloid progenitors invariably retained an intact Ptpn11 allele despite uniform activation of the conditional KrasG12D allele. These data suggested that there was strong selective pressure to retain a functional Ptpn11 allele despite oncogenic K-Ras expression. To test this hypothesis directly, we enumerated myeloid progenitor colonies in methylcellulose medium immediately after inactivating Ptpn11 and activating KrasG12D via retroviral transduction. This confirmed a strong dependence on SHP-2 for formation of myeloid colonies either in the presence or absence of KrasG12D. Infecting Ptpn11flox/flox, LSL-KrasG12D cells with a Ptpn11-IRES-Cre virus fully restored the aberrant growth phenotype of KrasG12D mutant cells. Remarkably, alleles encoding phosphatase-deficient SHP-2 proteins also rescued CFU-GM growth. These data indicate that SHP-2 is required for growth of both normal and neoplastic myeloid progenitors in vivo and in vitro. Our data support a model in which SHP-2 has essential hematopoietic functions that are independent of Ras activation and do not require SHP-2 phosphatase activity. The presence of protein-protein interaction domains in SHP-2 suggests that it may have a noncatalytic adaptor function. Because transformation by leukemogenic Ptpn11 alleles requires catalytic activity, our data imply that inhibition of SHP-2 catalysis will selectively target neoplastic hematopoietic progenitors.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
    In: Pediatric Blood & Cancer, Wiley, Vol. 70, No. 6 ( 2023-06)
    Abstract: Venetoclax is frequently used as salvage treatment in pediatric, adolescent, and young adult (AYA) patients with advanced hematologic malignancies. However, more data are needed from real‐world studies to guide the safe and appropriate use of venetoclax in this population. Procedure We retrospectively reviewed the medical records of all patients diagnosed with hematologic malignancies less than 30 years of age treated with venetoclax outside of clinical trials at the University of California San Francisco Benioff Children's Hospitals from 2016 to 2022. Results We identified 13 patients (acute myeloid leukemia , n  = 8; B‐acute lymphoblastic leukemia, n  = 3; myelodysplastic syndrome, n  = 2) aged 4 months to 27 years. A median of 3 prior lines of therapy weregiven (range 0–5). All patients received venetoclax in combination with either a hypomethylating agent or conventional chemotherapy. Three (23%) patients achieved complete remission (CR); two (15%) achieved partial remission (PR); 3 (23%) had stable disease (SD), and five (42%) had progressive disease. Median survival and time to progression from venetoclax initiation was 9 months (range 2.5–52 months) and 3 months (range 2 weeks to 7.5 months), respectively. Six patients (46%) developed grade 3 or higher infections while receiving venetoclax, including bacteremia due to atypical organisms, invasive pulmonary infections with Aspergillus, cytomegalovirus (CMV) viremia, skin infections, and encephalitis with bacterial brain abscesses. Conclusions Venetoclax in combination with hypomethylating agents or cytotoxic chemotherapy was effective in a subset of pediatric/AYA patients with advanced hematologic malignancies, but multiple severe infections were observed, particularly among patients who received venetoclax in combination with chemotherapy. Prospective studies will be required to determine the optimal dose and duration of venetoclax in this population.
    Type of Medium: Online Resource
    ISSN: 1545-5009 , 1545-5017
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2130978-4
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  • 5
    Online Resource
    Online Resource
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 3517-3517
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 3517-3517
    Abstract: Oncogenic mutations in NRAS or KRAS2 are found in 20–40% of myeloid malignancies including acute myeloid leukemia, high risk subtypes of myelodysplastic syndrome, and in juvenile myelomonocytic leukemia (JMML) and other types of MPD. Mutant Ras proteins accumulate in the active, GTP-bound state due to impaired intrinsic GTPase activity and resistance to GTPase activating proteins (GAPs). Alternative genetic mechanisms, such as BCR-ABL fusion and inactivation of the NF1 tumor suppressor, also deregulate Ras signaling in myeloid malignancies. Moreover, the association of germline mutations in NF1 with a markedly increased risk of JMML and studies of KrasG12D and Nf1 mutant mice argue strongly that hyperactive Ras can initiate MPD in vivo. Activating mutations in PTPN11, which encodes the tyrosine phosphatase SHP-2, comprise the most frequent genetic lesion in JMML. As is the case for NF1, germline PTPN11 mutations impart an increased risk of developing JMML. These observations imply that PTPN11 functions in a common genetic pathway with RAS and NF1. While NF1 encodes a GAP for Ras that directly reduces Ras-GTP levels, data from various systems have shown that SHP-2 is a positive effector of Ras activation. However, exactly how depohsophorylation of SHP-2 substrates regulates Ras output and how other SHP-2 target proteins modulate its effects are incompletely understood. Studies of Ptpn11 mutant embryos and of chimeric mice have shown that SHP-2 plays an essential role in hematopoietic development. To test the hypothesis that Ras is strictly downstream of SHP-2 in primary hematopoietic cells, we used the conditional alleles LSL-KrasG12D and Ptpn11flox/flox coupled with the interferon-inducible Mx1-Cre transgene. Juvenile mice were injected with pI:pC, resulting in expression of K-RasG12D and inactivation of Ptpn11. These mice uniformly developed fatal MPD similar to what we previously reported in Mx1-Cre, LSL-KrasG12D mice (Braun et al., PNAS 101(2):597–602), although with slightly increased latency. Importantly, however, myeloid progenitors invariably retained at least one functional Ptpn11 allele despite uniform activation of the conditional KrasG12D allele. These data suggested that there was strong selective pressure to retain at least one functional Ptpn11 allele, even in the presence of oncogenic K-Ras expression. To address this hypothesis directly, we infected LSL-KrasG12D, Ptpn11flox/flox, and compound mutant fetal liver cells with a Cre-expressing retrovirus and enumerated myeloid progenitor colonies in methylcellulose medium. Remarkably, no granulocyte-macrophage colonies developed from Cre-expressing Ptpn11flox/flox fetal liver cells either in the presence or absence of KrasG12D. Infecting compound mutant cells with a Ptpn11-IRES-Cre virus fully restored the aberrant growth phenotype of KrasG12D mutant cells. These data indicate that SHP-2 is required for growth of both normal and neoplastic myeloid progenitors in vivo and in vitro. Our data support a model in which SHP-2 has essential Ras-independent functions in hematopoiesis (i.e. that Ras is not strictly downstream of SHP-2). SHP-2 may be required either for efficient activation of canonical Ras effector pathways and/or to regulate signaling parallel to Ras. Our data imply that SHP-2 inhibition will ablate both normal and neoplastic hematopoietic progenitors. This may have a therapeutic role in preparing patients with JMML and other high risk MPDs for hematopoietic stem cell transplantation.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 6
    In: Science Signaling, American Association for the Advancement of Science (AAAS), Vol. 6, No. 304 ( 2013-12-03)
    Abstract: Oncogenic K-Ras proteins, such as K-Ras G12D , accumulate in the active, guanosine triphosphate (GTP)–bound conformation and stimulate signaling through effector kinases. The presence of the K-Ras G12D oncoprotein at a similar abundance to that of endogenous wild-type K-Ras results in only minimal phosphorylation and activation of the canonical Raf–mitogen-activated or extracellular signal–regulated protein kinase kinase (MEK)–extracellular signal–regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K)–Akt–mammalian target of rapamycin (mTOR) signaling cascades in primary hematopoietic cells, and these pathways remain dependent on growth factors for efficient activation. We showed that phospholipase C–γ (PLC-γ), PI3K, and their generated second messengers link activated cytokine receptors to Ras and ERK signaling in differentiated bone marrow cells and in a cell population enriched for leukemia stem cells. Cells expressing endogenous oncogenic K-Ras G12D remained dependent on the second messenger diacylglycerol for the efficient activation of Ras-ERK signaling. These data raise the unexpected possibility of therapeutically targeting proteins that function upstream of oncogenic Ras in cancer.
    Type of Medium: Online Resource
    ISSN: 1945-0877 , 1937-9145
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2013
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  • 7
    In: Nature Genetics, Springer Science and Business Media LLC, Vol. 42, No. 9 ( 2010-9), p. 794-800
    Type of Medium: Online Resource
    ISSN: 1061-4036 , 1546-1718
    RVK:
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2010
    detail.hit.zdb_id: 1494946-5
    SSG: 12
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  • 8
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  • 9
    Online Resource
    Online Resource
    American Society of Hematology ; 2019
    In:  Blood Advances Vol. 3, No. 22 ( 2019-11-26), p. 3575-3578
    In: Blood Advances, American Society of Hematology, Vol. 3, No. 22 ( 2019-11-26), p. 3575-3578
    Abstract: This is the first-ever demonstration of successful treatment of paroxysmal cold hemoglobinuria using the complement inhibitor eculizumab.
    Type of Medium: Online Resource
    ISSN: 2473-9529 , 2473-9537
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
    detail.hit.zdb_id: 2876449-3
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  • 10
    Online Resource
    Online Resource
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 778-778
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 778-778
    Abstract: NRAS and KRAS encode small GTPases that act as switches controlling cell fate. Mutations in these genes are commonly found in hematopoietic malignancies, and produce proteins maintained in an active, GTP-bound state. We have shown that mice expressing a mutant KrasG12D allele from the endogenous locus develop an aggressive myeloproliferative disease (MPD) that closely resembles human juvenile and chronic myelomonocytic leukemias (JMML and CMML). This model accurately reflects the relentless progression of JMML, which almost always recurs even after chemotherapy-induced remission; we therefore hypothesized that leukemia-initiating cells in this model must out-compete wild type hematopoietic stem cells (HSC) in vivo. Animal models of leukemogenesis support potential roles for either primitive HSC or committed progenitor cells as leukemia stem cells. To identify the leukemia stem cells in KrasG12D mice, sorted common myeloid progenitors (CMP), short-term hematopoietic stem cells (ST-HSC), or long-term hematopoietic stem cells (LT-HSC) were transplanted into lethally irradiated recipients. Mice receiving K-RasG12D-expressing CMP and ST-HSC showed early spleen colony formation but no graft-derived hematopoiesis by one month after transplantation, and did not develop MPD. By contrast, mice receiving KrasG12D LT-HSC had a rapid expansion of graft-derived myeloid and T-cells. Interestingly, these mice all died within 3 months, having developed KrasG12D acute T-lineage malignancies. To test directly how oncogenic K-Ras affects HSC function, we performed a limit dilution analysis to quantify transplantable HSC numbers. Mx1Cre; KrasG12D mice had ten-fold fewer bone marrow competitive repopulating units (CRU) than wild type; a two-fold difference could be attributed to total numbers of immunophenotypic HSC. Importantly, however, the LT-HSC of mice reconstituted by equal numbers of KrasG12D and wild type LT-HSC were predominantly derived from the KrasG12D cells. This suggests that oncogenic Ras confers a proliferative advantage in the LT-HSC compartment and is consistent with the idea that RAS mutation initiates MPD. Entry into the cell cycle is regulated by Ras signaling in a variety of cellular contexts and could also underlie both expansion and reduced engraftment of HSC. We determined the cell cycle status of LT-HSC in Mx1Cre; KrasG12D mice. Although wild type HSC were predominantly in G0, as reported, K-RasG12D-expressing LT-HSC were preferentially in cycle (G0 fraction 82% +/− 8.2% vs. 44% +/− 7.7%, p 〈 0.01). Preliminary gene expression analysis in sorted LT-HSC suggests that this may be mediated by increased transcription of cyclin D1 and cyclin E2. Collectively, these data show that LT-HSC expressing K-RasG12D can initiate fatal MPD and acute T-lineage leukemia. While hyperactive Ras decreases the number of engraftable LT-HSC, this is likely a cell-extrinsic effect as K-RasG12D-expressing LT-HSC outperform wild type LT-HSC in competitive repopulation assays. Importantly, Ras-mediated increases in cell cycling do not lead to post-transplant depletion of HSC. Ongoing tests of self-renewal in KrasG12D LT-HSC may help describe this key feature of many human malignancies - hyperproliferation without exhaustion - and provide targets for cancer stem cell directed therapy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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