The Grb-2 associated binder (Gab) family of scaffolding/adaptor/docking proteins is a group of three molecules with significant roles in cytokine receptor signaling. Gabs possess structural motifs for phosphorylation-dependent receptor recruitment, Grb2 binding, and activation of downstream signaling pathways through p85 and SHP-2. In addition, Gabs participate in hematopoiesis and regulation of immune response which can be aberrantly activated in cancer and inflammation. The multifunctionality of Gab adapters might suggest that they would be too difficult to consider as candidates for &#8220;targeted&#8221; therapy. However, the one drug/one target approach is giving way to the concept of one drug/multiple target approach since few cancers are addicted to a single signaling molecule for survival and combination drug therapies can be problematic. In this paper, we cover recent findings on Gab multi-functionality, binding partners, and their role in hematological malignancy and examine the concept of Gab-targeted therapy.

Sheetal Verma

Tamisha Vaughan

Kevin D. Bunting

Gab Adapter Proteins as Therapeutic Targets for Hematologic Disease

In the last years, several studies of molecular profiling of aggressive lymphomas were performed. In particular, it was shown that DLBCL can be distinguished in two different entities according to GEP. Specifically, ABC and GCB subtypes were characterized by having different pathogenetic and clinical features. In addition, it was demonstrated that DLBCLs are distinct from BL. Indeed, the latter is a unique molecular entity. However, relevant pathological differences emerged among the clinical subtypes. More recently, microRNA profiling provided further information concerning BL-DLBCL distinction as well as for their subclassification. In this paper, the authors based on their own experience and the most updated literature review, the main concept on molecular profiling of aggressive lymphomas.

Maura Rossi

Maria Antonella Laginestra

Anna Gazzola

Maria Rosaria Sapienza

Stefano A. Pileri

Pier Paolo Piccaluga

Molecular Profiling of Aggressive Lymphomas

<i  >Background</i>. The outcome of HIV-associated non-Hodgkin lymphoma (NHL) has improved substantially in the highly active antiretroviral therapy (HAART) era. However, HIV-Burkitt lymphoma (BL), which accounts for up to 20&#x25; of HIV-NHL, has poor outcome with standard chemotherapy. <i  >Patients and Methods</i>. We retrospectively reviewed HIV-BL treated in the HAART era with the Magrath regimen (CODOX-M/IVAC<svg style="vertical-align:-0.3003pt;width:10.1px;" id="M1" height="9.5625" version="1.1" viewBox="0 0 10.1 9.5625" width="10.1"      xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,0,0,-.017,.062,9.125)"><path id="xB1" d="M535 290h-212v-206h-58v206h-213v50h213v193h58v-193h212v-50zM535 -22h-483v50h483v-50z"/></g>

		
	
</svg>R) at four Canadian centres. <i  >Results</i>. Fourteen patients with HIV-BL received at least one CODOX-M/IVAC<svg style="vertical-align:-0.3003pt;width:10.1px;" id="M2" height="9.5625" version="1.1" viewBox="0 0 10.1 9.5625" width="10.1"      xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,0,0,-.017,.062,9.125)"><use xlink:href="#xB1"/></g>

		
	
</svg>R treatment. Median age at BL diagnosis was 45.5 years, CD4 count 375 cells/mL and HIV viral load (VL) &#x3c;50&#x2009;copies/mL. Patients received PCP prophylaxis and G-CSF, 13 received HAART with chemotherapy and 10 rituximab. There were 63 episodes of toxicity, none fatal, including: bacterial infection, <svg style="vertical-align:-0.1638pt;width:44.400002px;" id="M3" height="11.125" version="1.1" viewBox="0 0 44.400002 11.125" width="44.400002"      xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,0,0,-.017,.062,10.863)"><path id="x1D45B" d="M495 86q-46 -47 -87 -72.5t-63 -25.5q-43 0 -16 107l49 210q7 34 8 50.5t-3 21t-13 4.5q-35 0 -109.5 -72.5t-115.5 -140.5q-21 -75 -38 -159q-50 -10 -76 -21l-6 8l84 340q8 35 -4 35q-17 0 -67 -46l-15 26q44 44 85.5 70.5t64.5 26.5q35 0 10 -103l-24 -98h2&#xD;&#xA;q42 56 97 103.5t96 71.5q46 26 74 26q9 0 16 -2.5t14 -11.5t9.5 -24.5t-1 -44t-13.5 -68.5q-30 -117 -47 -200q-4 -19 -3.5 -25t6.5 -6q21 0 70 48z"/></g><g transform="matrix(.017,0,0,-.017,13.305,10.863)"><path id="x3D" d="M535 323h-483v50h483v-50zM535 138h-483v50h483v-50z"/></g><g transform="matrix(.017,0,0,-.017,28.008,10.863)"><path id="x32" d="M412 140l28 -9q0 -2 -35 -131h-373v23q112 112 161 170q59 70 92 127t33 115q0 63 -31 98t-86 35q-75 0 -137 -93l-22 20l57 81q55 59 135 59q69 0 118.5 -46.5t49.5 -122.5q0 -62 -29.5 -114t-102.5 -130l-141 -149h186q42 0 58.5 10.5t38.5 56.5z"/></g><g transform="matrix(.017,0,0,-.017,36.168,10.863)"><path id="x30" d="M241 635q53 0 94 -28.5t63.5 -76t33.5 -102.5t11 -116q0 -58 -11 -112.5t-34 -103.5t-63.5 -78.5t-94.5 -29.5t-95 28t-64.5 75t-34.5 102.5t-11 118.5q0 58 11.5 112.5t34.5 103t64.5 78t95.5 29.5zM238 602q-32 0 -55.5 -25t-35.5 -68t-17.5 -91t-5.5 -105&#xD;&#xA;q0 -76 10 -138.5t37 -107.5t69 -45q32 0 55.5 25t35.5 68.5t17.5 91.5t5.5 105t-5.5 105.5t-18 92t-36 68t-56.5 24.5z"/></g>

		
	
</svg>; grade 3-4 hematologic toxicity, <svg style="vertical-align:-0.1638pt;width:44.400002px;" id="M4" height="11.125" version="1.1" viewBox="0 0 44.400002 11.125" width="44.400002"      xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,0,0,-.017,.062,10.863)"><use xlink:href="#x1D45B"/></g><g transform="matrix(.017,0,0,-.017,13.305,10.863)"><use xlink:href="#x3D"/></g><g transform="matrix(.017,0,0,-.017,28.008,10.863)"><path id="x31" d="M384 0h-275v27q67 5 81.5 18.5t14.5 68.5v385q0 38 -7.5 47.5t-40.5 10.5l-48 2v24q85 15 178 52v-521q0 -55 14.5 -68.5t82.5 -18.5v-27z"/></g><g transform="matrix(.017,0,0,-.017,36.168,10.863)"><path id="x34" d="M456 178h-96v-72q0 -51 12.5 -62.5t72.5 -16.5v-27h-256v27q65 5 78 17t13 62v72h-260v28q182 271 300 426h40v-407h96v-47zM280 225v295h-2q-107 -148 -196 -295h198z"/></g>

		
	
</svg>; febrile neutropenia, <svg style="vertical-align:-0.1638pt;width:36.237499px;" id="M5" height="10.925" version="1.1" viewBox="0 0 36.237499 10.925" width="36.237499"      xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,0,0,-.017,.062,10.65)"><use xlink:href="#x1D45B"/></g><g transform="matrix(.017,0,0,-.017,13.305,10.65)"><use xlink:href="#x3D"/></g><g transform="matrix(.017,0,0,-.017,28.008,10.65)"><path id="x37" d="M447 623l8 -12l-283 -613l-74 -10l-7 11q174 283 297 551h-216q-48 0 -62.5 -12t-33.5 -63h-29q10 60 18 148h382z"/></g>

		
	
</svg>; oral thrush; and ifosfamide neurological toxicity, <svg style="vertical-align:-0.1638pt;width:36.237499px;" id="M6" height="11.125" version="1.1" viewBox="0 0 36.237499 11.125" width="36.237499"      xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,0,0,-.017,.062,10.863)"><use xlink:href="#x1D45B"/></g><g transform="matrix(.017,0,0,-.017,13.305,10.863)"><use xlink:href="#x3D"/></g><g transform="matrix(.017,0,0,-.017,28.008,10.863)"><use xlink:href="#x31"/></g>

		
	
</svg> each. At a median followup of 11.7 months, 12 (86&#x25;) patients are alive and in remission. All 10 
patients who received HAART, chemotherapy, and rituximab are alive. CD4 counts and HIV VL 6 months following BL therapy completion (<svg style="vertical-align:-0.1638pt;width:36.237499px;" id="M7" height="10.925" version="1.1" viewBox="0 0 36.237499 10.925" width="36.237499"      xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,0,0,-.017,.062,10.65)"><use xlink:href="#x1D45B"/></g><g transform="matrix(.017,0,0,-.017,13.305,10.65)"><use xlink:href="#x3D"/></g><g transform="matrix(.017,0,0,-.017,28.008,10.65)"><path id="x35" d="M153 550l-26 -186q79 31 111 31q90 0 141.5 -51t51.5 -119q0 -93 -89 -166q-85 -69 -173 -71q-32 0 -61.5 11.5t-41.5 23.5q-18 17 -17 34q2 16 22 33q14 9 26 -1q61 -50 124 -50q60 0 93 43.5t33 104.5q0 69 -41.5 110t-121.5 41q-53 0 -102 -20l38 305h286l6 -8&#xD;&#xA;l-26 -65h-233z"/></g>

		
	
</svg> patients) were &#x3e;250 cells/mL 
and undetectable, respectively, in 4. <i  >Conclusion</i>. 
Intensive chemotherapy with 
CODOX-M/IVAC<svg style="vertical-align:-0.3003pt;width:10.1px;" id="M8" height="9.5625" version="1.1" viewBox="0 0 10.1 9.5625" width="10.1"      xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,0,0,-.017,.062,9.125)"><use xlink:href="#xB1"/></g>

		
	
</svg>R 
yielded acceptable toxicity and good survival rates in patients 
with HIV-associated Burkitt lymphoma receiving 
HAART.

J. A. Rodrigo

L. K. Hicks

M. C. Cheung

K. W. Song

H. Ezzat

C. S. Leger

J. Boro

J. S. G. Montaner

M. Harris

H. A. Leitch

HIV-Associated Burkitt Lymphoma: Good Efficacy and Tolerance of Intensive Chemotherapy Including CODOX-M/IVAC with or without Rituximab in the HAART Era

Significant advances in our understanding of the genetic defects and the pathogenesis of juvenile myelomonocytic leukemia (JMML) have been achieved in the last several years. The information gathered tremendously helps us in designing molecular targeted therapies for this otherwise fatal disease. Various approaches are being investigated to target defective pathways/molecules in this disease. However, effective therapy is still lacking. Development of specific target-based drugs for JMML remains a big challenge and represents a promising direction in this field.

Xiaoling Liu

Himalee Sabnis

Cheng-Kui Qu

Molecular Targets for the Treatment of Juvenile Myelomonocytic Leukemia

An elevated serum level of NM23-H1 protein is a poor prognostic factor in patients with various hematologic malignancies. The extracellular NM23-H1 protein promotes the <i>in vitro</i> growth and survival of acute myelogenous leukemia (AML) cells and inversely inhibits the <i>in vitro</i> survival of normal peripheral blood monocytes in primary culture at concentrations equivalent to the levels found in the serum of AML patients. The growth and survival promoting activity to AML cells is associated with cytokine production and activation of mitogen-activated protein kinases (MAPKs) and signal transducers and activators of transcription (STAT) signaling pathways. Inhibitors specific for MAPK signaling pathways inhibit the growth/survival-promoting activity of NM23-H1. These findings indicate a novel biological action of extracellular NM23-H1 and its association with poor prognosis. These results suggest an important role of extracellular NM23-H1 in the malignant progression of leukemia and a potential therapeutic target for these malignancies.

Junko Okabe-Kado

Takashi Kasukabe

Yasuhiko Kaneko

Extracellular NM23 Protein as a Therapeutic Target for Hematologic Malignancies

The disturbance of apoptosis molecular signaling pathways is involved in carcinogenesis. BCL2 family of proteins is the hallmark of apoptosis regulation. In the last decade, new members of <i>BCL2</i> gene family were discovered and cloned and were found to be differentially expressed in many types of cancer. BCL2 protein family, through its role in regulation of apoptotic pathways, is possibly related to cancer pathophysiology and resistance to conventional chemotherapy. It is well known that leukemias are haematopoietic malignancies characterized by biological diversity, varied cytogenetics, different immunophenotype profiles,  and diverse outcome. Current research focuses on the prognostic impact and specific role of these proteins in the pathogenesis of leukemias. The understanding of the molecular pathways that participate in the biology of leukemias may lead to the design of new therapies which may improve patients&#39; survival. In the present paper, we describe current knowledge on the role of BCL2 apoptosis regulator proteins in acute and chronic leukemias.

Flora Tzifi

Christina Economopoulou

Dimitrios Gourgiotis

Alexandros Ardavanis

Sotirios Papageorgiou

Andreas Scorilas

The Role of BCL2 Family of Apoptosis Regulator Proteins in Acute and Chronic Leukemias

B-cell chronic lymphocytic leukaemia (B-CLL) remains an incurable disease due to the high risk of relapse, even after complete remission, raising the need to control and eliminate residual tumor cells in long term. Adoptive T cell therapy with genetically engineered specificity is thought to fulfil expectations, and clinical trials for the treatment of CLL are initiated. Cytolytic T cells from patients are redirected towards CLL cells by ex vivo engineering with a chimeric antigen receptor (CAR) which binds to CD19 on CLL cells through an antibody-derived domain and triggers T cell activation through CD3<i>&#x3b6;</i> upon tumor cell engagement. Redirected T cells thereby target CLL cells in an MHC-unrestricted fashion, secret proinflammatory cytokines, and eliminate CD19<sup>+</sup> leukaemia cells with high efficiency. Cytolysis of autologous CLL cells by patient's engineered T cells is effective, however, accompanied by lasting elimination of healthy CD19<sup>+</sup> B-cells. In this paper we discuss the potential of the strategy in the treatment of CLL, the currently ongoing trials, and the future challenges in the adoptive therapy with CAR-engineered T cells.

Philipp Koehler

Patrick Schmidt

Andreas A. Hombach

Michael Hallek

Hinrich Abken

Engineered T Cells for the Adoptive Therapy of B-Cell Chronic Lymphocytic Leukaemia

In the recent years, the discovery of a series of mutations in patients with myeloid malignancies has provided insight into the pathogenesis of myelodysplastic syndromes (MDSs), myeloproliferative neoplasms (MPNs), and acute myeloid leukemia (AML). Among these alterations have been mutations in genes, such as <i  >IDH1/2</i>, <i  >TET2</i>, <i  >DNMT3A</i>, and <i  >EZH2</i>, which appear to affect DNA and/or histone lysine methylation. Large clinical correlative studies are beginning to decipher the clinical importance, prevalence, and potential prognostic significance of these mutations. Additionally, burgeoning insight into the role of epigenetics in the pathogenesis of myeloid malignancies has prompted increased interest in development of novel therapies which target DNA and histone posttranslational modifications. DNA demethylating agents have been demonstrated to be clinically active in a subset of patients with MDS and AML and are used extensively. However, newer, more specific agents which alter DNA and histone modification are under preclinical study and development and are likely to expand our therapeutic options for these diseases in the near future. Here, we review the current understanding of the clinical importance of these newly discovered mutations in AML and MDS patients. We also discuss exciting developments in DNA methyltransferase inhibitor strategies and the prospect of novel histone lysine methyltransferase inhibitors.

Amir T. Fathi

Omar Abdel-Wahab

Mutations in Epigenetic Modifiers in Myeloid Malignancies and the Prospect of Novel Epigenetic-Targeted Therapy

Despite the fact that the majority of lymphomas initially respond to treatment, many patients relapse and die from disease that is refractory to current regimens. The need for new treatment strategies in lymphomas has led to the investigation and evaluation of novel agents that target cellular pathways. The mammalian target of rapamycin (mTOR) is a representative pathway that may be implicated in lymphomagenesis. Rapamycin and especially its derivatives (temsirolimus, everolimus, and deforolimus) represent the first described mTOR inhibitors. These agents have shown promising results in the treatment of lymphoid malignancies. On the other hand, new ATP-competitive mTOR inhibitors that provoke a broader inhibition of mTOR activity are in early stages of clinical development. The purpose of this paper is to summarize the existing knowledge about mTOR inhibitors and their use in the treatment of B-cell lymphomas. Relevant issues regarding mTOR biology in general as well as in B-cell lymphoid neoplasms are also discussed in short.

Pinelopi Argyriou

Panagiota Economopoulou

The Role of mTOR Inhibitors for the Treatment of B-Cell Lymphomas

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<p><em>Advances in Hematology</em> publishes original research articles and&nbsp;review articles in all areas of hematology.</p>


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Advances in Hematology - Table of contents 2012

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Advances in Hematology publishes original research articles and review articles in all areas of hematology.

Advances in Hematology