Aetiology and Genetics of Haematological Malignancies

Comprehensive fill-in-the-blank practice flashcards covering haematological malignancies, haematopoiesis, cell cycle checkpoints, oncogenes, tumour suppressor pathways, and epigenetic modifications.

Haematological malignancies are defined as clonal disorders of haemopoietic __________ or progenitor cells.

stem

Unlike solid tumours that typically present as a localized mass, haemopoietic neoplasms arise from blood-forming and lymphoid tissues and frequently exhibit __________ disease at presentation.

widespread

In classical hematology, haematological malignancies are broadly classified into three major groups: leukemias, lymphomas, and __________.

multiple myeloma

William Dameshek introduced the classification of myeloproliferative disorders in 1951, but the terminology was later altered after Nowell and Hungerford discovered the __________ chromosome.

Philadelphia

In healthy adults, normal haematopoiesis produces approximately __________ to __________ blood cells daily to replace senescent cells.

$10^{11}$ to $10^{12}$

The property of haematopoietic stem cells (HSCs) to reside within specialised bone marrow niches is termed __________.

homing

During normal haemopoiesis, the primary function of Stem Cell Factor (SCF) is to promote __________.

stem cell survival

In the regulation of haemopoiesis, interleukin-3 (IL-3) primarily modulates __________.

early progenitor proliferation

While G-CSF selectively stimulates neutrophil production, GM-CSF stimulates the production of __________.

granulocytes and monocytes

In the cell cycle, the resting phase in which cells remain alive but are not dividing is designated as the __________.

$$G_0\text{ phase}$$

Progression through the S phase of the cell cycle is driven by the __________ complex.

Cyclin A-CDK2

Progression through the M phase of the cell cycle is driven by the cyclin-CDK complex __________.

Cyclin B-CDK1 (MPF)

At the G2 checkpoint, sensors ATM, ATR, Chk1, and Chk2 signal effectors p53 and p21 to target __________ inhibition, keeping CDK1 inactive.

Cdc25C

Negative regulators of the G1 checkpoint (Restriction Point) include $p16^{\text{INK4a}}$, p21, p27, and __________.

p57

The oncogene BCR-ABL1 is classically associated with __________.

Chronic Myeloid Leukaemia

The oncogene MYC is typically associated with Burkitt Lymphoma, whereas JAK2 mutations are associated with __________.

Myeloproliferative Neoplasms

The tumour suppressor gene TP53 is widely referred to as the '__________'.

guardian of the genome

Histone acetyltransferases (HATs) catalyze the transfer of an acetyl group from acetyl-CoA to __________ residues on histone proteins.

lysine

Histone acetylation neutralizes the positive charge on lysine residues, relaxing chromatin into transcriptionally active __________.

euchromatin

Histone Deacetylases (HDACs) remove acetyl groups from histones, restoring positive charges and resulting in condensed chromatin and __________.

gene silencing

In Acute Myeloid Leukaemia, the fusion protein RUNX1::RUNX1T1 (AML1-ETO) recruits HDACs to promoter regions, causing a maturation arrest and accumulation of __________.

myeloblasts

In acute promyelocytic leukaemia, the PML::RARA fusion protein recruits HDAC-containing complexes, which can be disrupted by treatment with __________ and arsenic trioxide.

all-trans retinoic acid (ATRA)

DNA methylation involves the covalent addition of a methyl group to the 5-carbon position of cytosine residues within CpG dinucleotides, yielding __________.

5-methylcytosine

The enzyme responsible for copying and maintaining existing DNA methylation patterns during replication is __________.

DNMT1

The establishment of new methylation patterns during embryogenesis and differentiation is catalyzed by the de novo methyltransferases __________ and __________.

DNMT3A and DNMT3B

Active DNA demethylation is initiated by the __________ family of enzymes, which oxidize 5-methylcytosine.

TET (Ten-Eleven Translocation)

According to the histone methylation transcriptional rules, methylation at H3K4 activates transcription ('ON'), whereas methylation at H3K27 and __________ represses transcription ('OFF').

H3K9

EZH2, a component of Polycomb Repressive Complex 2, functions as a __________.

histone methyltransferase (HMT)

Myelodysplastic Syndromes (MDS) frequently exhibit global DNA hypermethylation, providing the rationale for treatment with __________ agents.

hypomethylating

Normal cellular genes that control cell growth, proliferation, differentiation, and survival before becoming oncogenic through mutation are termed __________.

proto-oncogenes

The CCND1 proto-oncogene encodes Cyclin D1, which promotes $G_1$ progression by activating __________.

CDK4/6

Following DNA damage, activation of p53 induces the expression of CDKN1A ($p21$), preventing phosphorylation of RB, which inhibits the transcription factor __________ and blocks S-phase entry.

E2F

Upon growth factor withdrawal, elevated levels of the cyclin-dependent kinase inhibitor __________ inhibit CDK2/CDK4 to enforce $G_1$ arrest.

p27

In Chronic Lymphocytic Leukaemia (CLL), reduced expression of the cell cycle inhibitor __________ is associated with more aggressive disease and shorter progression-free survival.

p27

The three fundamental pathogenic mechanisms of malignant transformation in haematological malignancies are uncontrolled proliferation, inhibition of apoptosis, and __________.

inhibition of maturation

In the diagram of normal haematopoiesis, the common stem cell that diverges into both the common myeloid progenitor and the common lymphoid progenitor is the __________.

Multipotential hematopoietic stem cell (Hemocytoblast)

In the cell cycle checkpoints diagram shown, the checkpoint designated for repairing damaged DNA and rectifying errors during DNA replication is the __________.

S Checkpoint

According to the detailed cell cycle control diagram, the spindle assembly checkpoint (M checkpoint) utilizes Mad2, BubR1, Bub3, and Mps1 as sensors, and acts via the effector __________ to target separase.

APC/C