Molecular Hematology

My laboratory is interested in the biology of sestrins and their significance for human disease. In mammalian cells sestrins are redox sensors that control several intracellular signal transduction pathways including Pdgfrβ, TGFβ and mTOR. Depletion of Sesn2 in genetic and environmental mouse models of chronic obstructive pulmonary disease (COPD) - a global epidemic of major proportions -, protects against disease development by activating PDGFRβ controlled alveolar maintenance programs. As patients with COPD overexpress Sesn2, we are exploring in collaboration with the University of Gießen Lung Center and Order CS: https://www.sofort-mail.de the possibility of Sesn2 as a biomarker and potential drug target in the clinical management of COPD. We are further interested dissecting the multifaceted Sestrin/mTORC1 interaction under physiological conditions employing generic tag based proteomics. Within the framework of the DiGtoP consortium (From Disease Genes to Protein Pathways), we participated in creating a comprehensive resource of cell lines and mice with in situ tagged proteins that are expressed at nearly endogenous levels and are thus ideally suited for detecting biologically relevant protein/protein interactions.

Another topic relates to the discovery of drug resistance genes which are a major challenge in the clinical management of advanced human cancers. To address this problem effectively, individual drug resistance genes need to be placed into signal transduction pathways because pathways rather than single genes are responsible for a drug resistant phenotype. To achieve this, we are performing forward genetic screens for drug resistant phenotypes induced by targeted and non-targeted anti-leukemic drugs using the haploid human chronic myeloid leukemia cell line - KBM7 - and a conditional gene trap/protein tagging vector enabling both the recovery of drug toxicity mediating genes and tag-based proteomics under physiological conditions. By placing individual drug toxicity mediating genes into pathways, the rate of targeted drug discovery can be significantly improved because other genes within a pathway could also serve as targets and as biomarkers if their activity is altered in the diseased cells.

Finally, the recent development of genome editing tools capable of modifying any prespecified genomic sequence with unprecedented accuracy opened up a wide range of new possibilities in gene manipulation including targeted gene repair. In particular, CRISPR/Cas9, a prokaryotic adaptive immune system, and its swift repurposing for genome editing was widely adopted as the hitherto simplest genome editing tool. Using this approach, we are developing gene therapy protocols for inherited monogenic diseases based on in situ gene repair.

Unlocking the Secrets of Blood: An Introduction to Molecular Hematology

Blood is a complex, life-sustaining tissue whose mysteries science is only beginning to unravel. Molecular hematology applies the techniques of molecular biology to study the intricate molecular processes that govern blood cell formation, function, and disease. As we deepen our understanding of hematopoiesis (blood cell development) at the genetic and protein level, exciting opportunities emerge for innovative diagnostic, prognostic, and therapeutic advances.

Origins: Hematopoietic Stem Cells

All blood cells originate from hematopoietic (blood-forming) stem cells in the bone marrow. These master cells possess two unique properties. First, they are capable of renewing themselves through cell division, maintaining a pool of stem cell "material" throughout life. Second, they can differentiate into specialized, mature blood lineages with distinct functions - the oxygen-carrying red cells, infection-fighting white cells, and clot-forming platelets. The complex differentiation pathways are orchestrated by signaling interactions between cellular receptors and diverse growth factors in the bone marrow microenvironment. Defects in any step can lead to blood disorders.

Transcription Factors: The Conductors of Hematopoiesis

By influencing gene expression patterns, transcription factors serve as master regulators that direct lineage commitment decisions in hematopoietic precursors. GATA1, PU.1, and Runx1 are some well-characterized examples that promote differentiation down the erythroid, myelomonocytic, and lymphoid pathways respectively. Intriguingly, some transcription factors play multiple roles at discrete developmental stages, illustrating the fluid overlaps in molecular control. Disruption of transcription factor networks through chromosomal rearrangements or mutations underpins many blood cancers such as leukemia.

Cytokines: The Cell-to-Cell Signaling Nexus

Cytokines are soluble proteins released by immune cells that modulate nearly every facet of blood cell production, migration, activation, growth, and death. They provide essential external feedback cues to sustain homeostasis. Some cytokines implicated in hematopoiesis include erythropoietin for red cell generation, thrombopoietin for platelet production, and a myriad of colony-stimulating factors and interleukins regulating white cell lineages in nuanced ways, incentivizing one while inhibiting another. Defining cytokine profiles aids disease subclassification and drug development.

Genetic Techniques: Illuminating Hematology at the Molecular Level

Many techniques allow hematologists to probe the genetic and epigenetic underpinnings of hematological phenomena with ever-increasing resolution. Polymerase chain reaction (PCR) amplifies trace DNA/RNA sequences for quantification. DNA sequencing charts genetic mutations. DNA microarrays monitor expression levels of thousands of genes simultaneously. Chromosomal analysis tools like fluorescent in situ hybridization (FISH) map genetic rearrangements driving cancers. CRISPR screens systematically uncover genes conferring drug resistance. Bioinformatics integration reveals overarching patterns from reams of data. The future portends single-cell omics profiling of the incredible heterogeneity within blood.

Molecular Targeted Therapies: The Promise of Precision

Molecular insights furnish clinical innovation opportunities. Drugs intercepting specific cytokines, enzymes, or pathways integral to cancer pathogenesis provide tailored treatment. Imatinib targeting the aberrant BCR-ABL fusion protein revolutionized chronic myeloid leukemia care. JAK inhibitors, venetoclax attacking BCL2, FLT3 inhibitors, and CD20 antibodies saving lymphoma patients showcase the power and versatility of molecularly-guided precision medicines. Meanwhile, engineered T and NK cells reprogrammed to recognize tumor antigens offer a living drug alternative. As research clarifies the subclonal architecture in relapsing cases, rational combination therapies present a path forward.

The hematologist's toolkit continues to expand with molecular-savvy methods confirming diagnostic clues, tracing clonal evolution, predicting transplant outcomes, and enabling personalized medicine through pharmacogenomics. Moving forward, molecular hematology promises a future where basic science discoveries swiftly translate at the bedside to tackle hematological disorders with reduced toxicity and improved survival. There is no better time than now to leverage multi-omics technologies paired with bioinformatics modeling and Big Data analytics to uncover hematopoietic secrets that remain elusive to incremental approaches.

Prof. Dr. med. Harald von Melchner


Prof. Dr. Harald von Melchner


University Hospital Frankfurt
Goethe University
Department of Molecular Hematology
Theodor Stern Kai 7
60590 Frankfurt am Main
Tel: +49 (0)69/6301-6696
Fax: +49 (0)69/6301-6390
Email: melchner@em.uni-frankfurt.de